Clinical trial NCT02812706
Conditions: Multiple Myeloma
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2016-09-05; Completion date: 2022-09-28
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Primary Objectives:

* Phase I: To evaluate safety and tolerability of isatuximab in Japanese participants with relapsed and refractory multiple myeloma.
* Phase II: To evaluate efficacy of isatuximab at recommended dose and to further evaluate the overall response rate (ORR) of isatuximab in Japanese participants with relapsed and refractory multiple myeloma.

Secondary Objectives:

* To evaluate the safety including immunogenicity of isatuximab. The severity, frequency and incidence of all adverse events were assessed.
* To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing schedule.
* To assess the efficacy using International Myeloma Working Group (IMWG) uniform response criteria.
* To assess the relationship between Baseline cluster of differentiation 38 (CD38) receptor density on multiple myeloma cells and efficacy.

Detailed description:
The study duration for an individual participant included a screening period for inclusion of up to 21 days, the treatment period consisting of 28-day cycles and a follow-up period. Treatment with isatuximab might continue until disease progression, unacceptable adverse event, or other reason for discontinuation.

Arms: arm 1: Participants received Isatuximab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then every 2 weeks (Q2W) (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 112 weeks). arm 2: Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 137 weeks). arm 3: Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 248 weeks).
Interventions: intervention 1: Isatuximab SAR650984
Intervention descriptions: intervention 1: Pharmaceutical form: solution Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 


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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR 
 
Not Applicable 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
 
SPONSOR 
Company: 
 
Address: 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
Tel for 24 hours 
alerting system: 
 
 
FAX for Safety 
Emergency: 
E-mail: 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 05 
Japan only 
15-Jul-2020, Version number: 1 
(electronic 5.0) 
Amended Clinical Trial Protocol 04 
Japan only 
14-Dec-2018, Version number: 1 
(electronic 4.0) 
Amended Clinical Trial Protocol 03 
Japan only 
12-Oct-2017, Version number: 1 
(electronic 3.0) 
Protocol Amendment 03 
Japan only 
12-Oct-2017, Version number: 1 
(electronic 1.0)  
Amended Clinical Trial Protocol 02 
Japan only  
27-Jan-2017, Version number: 1 
(electronic 2.0)  
Protocol Amendment 02 
Japan only 
27-Jan-2017, Version number: 1 
(electronic 1.0)  
Amended Clinical Trial Protocol 01 
Japan only 
13-May-2016, Version number: 1 
(electronic 1.0)  
Protocol Amendment 01 
Japan only 
13-May-2016, Version number: 1 
(electronic 1.0)  
Clinical Trial Protocol 
Japan only 
01-Feb-2016, Version number: 1 
(electronic 1.0)  
 
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AMENDED PROTOCOL 05 (15-JUL-2020)  
OVERALL RATIONALE FOR THE AMENDMENT  
A risk of hepatitis reactivation has been identified in the SAR650984 Investigator’s Brochure 
edition 11 (30-Apr-2020). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.5 Study Flowchart – Phase 
II part; 1.6 Footnotes for 
Study Flowcharts; 6.6.3 
Guidance in case of hepatitis 
B reactivation occurring 
under study treatment 
Additional hepatitis viral serology if HBV status 
unknown before treatment start, to be repeated if 
clinically indicated. 
A risk of hepatitis reactivation has been 
identified. 
6.6.3 Guidance in case of 
hepatitis B reactivation 
occurring under study 
treatment 
Description of study treatment discontinuation and 
restart procedure in case of viral reactivation. 
A risk of hepatitis reactivation has been 
identified. 
6.6.3 Guidance in case of 
hepatitis B reactivation 
occurring under study 
treatment; 12.3.1 Day 1 of 
Each Cycle; 12.3.4 Day 15 
of Each Cycle 
Description of monitoring of alanine 
aminotransferase (ALT) and aspartate 
aminotransferase (AST) in case of viral 
reactivation. 
A risk of hepatitis reactivation has been 
identified. 
10.5.2 Serious Adverse 
Events, Adverse Events of 
Special Interest, Pregnancy 
and Symptomatic Overdose 
Hospitalization and exams report for serious 
adverse events (SAEs), adverse events of special 
interest (AESI), pregnancy and symptomatic 
overdose will not be systematically requested. 
Only necessary copies of medical records 
are to be shared with the Sponsor. 
Whole document 
Correction of typos. 
 
 
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CLINICAL TRIAL SUMMARY  
COMPOUND: isatuximab 
STUDY No: TED14095  
STUDY NAME: Islands 
TITLE 
A Phase I/ II Study of isatuximab (Anti-CD38 mAb) Administered as a Single 
Agent in Japanese Patients with Relapsed AND Refractory Multiple Myeloma 
INVESTIGATOR/TRIAL LOCATION 
Japan 
PHASE OF DEVELOPMENT 
Phase I and Phase II 
STUDY OBJECTIVE(S) 
 
Primary objective 
PHASE I PART 
• 
To evaluate safety and tolerability of isatuximab in Japanese 
patients with relapsed and refractory multiple myeloma. 
PHASE II PART 
• 
To evaluate efficacy of isatuximab at recommended dose and to 
further evaluate the overall response rate (ORR) of isatuximab in 
Japanese patients with relapsed and refractory multiple myeloma. 
Secondary objective(s)  
• 
To evaluate the safety including immunogenicity of isatuximab. The 
severity, frequency and incidence of all adverse events will be 
assessed. 
• 
To evaluate the pharmacokinetic (PK) profile of isatuximab in the 
proposed dosing schedule. 
• 
To assess the efficacy using International Myeloma Working Group 
(IMWG) uniform response criteria. 
• 
To assess the relationship between baseline CD38 receptor density 
(RD) on multiple myeloma cells and efficacy. 
 
Exploratory objective 
• 
To assess minimal residual disease (MRD) in patients achieving 
Complete Response (CR) and correlate with clinical outcome. 
• 
To investigate the relationship of soluble CD38 and parameters of 
PK and clinical response. 
• 
To investigate the relationship between multiple myeloma molecular 
subtype (as defined by cytogenetics/ FISH) and parameters of 
clinical response. 
• 
To investigate the relationship between immune genetic 
determinants, immune phenotype and parameters of clinical 
response. 
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STUDY DESIGN 
This is an open-label, non-randomized, single arm, local multi-center study 
conducted in 2 parts, Phase I and Phase II. 
In this study a cycle is 28 days. 
Phase I part 
The Phase I part is a dose escalation study of isatuximab administered as 
single agent as an intravenous (IV) infusion every week (QW) in Cycle 1 
(4 weeks) followed by every 2 weeks (Q2W) in subsequent cycles to adult 
multiple myeloma patients. The initial dose and schedule of administration will 
be based on those defined in TED10893 study. 
The maximum tolerated dose (MTD) is defined as one level lower dose of the 
Maximum Administrated Dose (MAD). 
Dose escalation will be stopped when the Cohort 1 dosing level is considered 
as a MAD defined as the dose at which ≥33% of evaluable patients have 
experienced a DLT following the first administration of IMP and occurring 
during the first cycle from a cohort of 3 to 6 patients. 
Cohort 1 and 2 will include at least 3 evaluable patients if no potential 
confirmed DLT is reported, or up to 6 evaluable patients if a potential DLT is 
experienced by 1 of the first 3 patients. 
In Cohort 1, at least 7 calendar days must pass after dosing the first patient 
before dosing the second patient. 
Dose level for Cohort 1 will be the 1/2 of the global maximum administrated 
dose defined in TED10893 study. Dose level for Cohort 2 will be same as 
global recommended dose: 
• 
Cohort 1:  
1/2 of global maximum administrated dose defined in TED10893 
(ie. 10 mg/kg QW in Cycle 1 (4 weeks) followed by 10 mg/kg Q2W 
in subsequent cycles) 
• 
Cohort 2:  
Global recommended dose defined in TED10893 
(ie. 20 mg/kg QW in Cycle 1 (4 weeks) followed by 20 mg/kg Q2W 
in subsequent cycles) 
Intrapatient dose escalation is not permitted. 
After completing the first cycle, patients may continue to receive additional 
administrations of isatuximab (at the same dosing level provided the patient is 
obtaining benefit from the treatment). If this dosing regimen is considered safe 
patients can continue the treatment (=isatuximab) until unacceptable adverse 
event, disease progression, withdrawal of consent and/or Investigator’s 
decision. Additionally PK, safety and disease response will be assessed. 
Upon completion of enrollment and DLT observation period (Cycle 1) in each 
cohort, the Study Committee will review collected data and will make the 
decision to continue the enrollment in subsequent cohort/ phase. 
Phase II part 
The Phase II part is to commence after the Cohort 2 of Phase I part has 
completed enrollment and DLT evaluation. Patients enrolled in Phase II part 
will be given at the recommended dose determined in Phase I part. 
STUDY POPULATION  
Selection criteria 
 
Inclusion criteria: 
I 01. 
Males or females, age 20 years or older. 
I 02. 
 Patient must have a known diagnosis of symptomatic multiple 
myeloma. 
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I 03. 
Patients must have received at least 3 prior lines of therapies which 
must include treatment with an Immunomodulatory Drug (IMiD) and 
a Proteasome Inhibitor (PI). The patients must have received an 
IMiD and a PI for ≥2 cycles or ≥2 months of treatment. 
OR 
Patients whose disease is double refractory to an IMiD and a PI.  
For patients who have received more than one type of IMiD and PI, 
their disease must be refractory to the most recent one. The patients 
must have received an IMiD and a PI for ≥2 cycles or ≥2 months of 
treatment. 
I 04. 
Subject must have been responsive to at least one prior line of 
therapy (MR or better). 
I 05. 
Refractory to the most recently received IMiD or PI included therapy. 
(Patient must progress during or within 60 days of completion of 
treatment with IMiD or PI) 
I 06. 
Patients with measurable disease defined as at least one of the 
followings: 
IgG Type: Serum M-protein ≥1 g/dL (≥10 g/L) 
IgA or D Type: Serum M-protein  ≥0.5 g/dL (≥5 g/L) 
Urine M-protein ≥200 mg/24 hours 
I 07. 
ECOG Performance status ≤2 
I 08. 
Life expectancy of at least 3 months. 
I 09. 
Female patients of childbearing potential (FCBP) and male patients 
with female partners of childbearing potential who agreed to avoid 
pregnancy by using an adequate method of contraception for 2 
weeks prior to screening, during and 6 months after the last 
administration of the IMP. Methods of contraception includes, 2-
barrier method or 1 barrier method with a spermicide (spermicide is 
only available for purchase with condoms or diaphragm), oral 
hormonal contraception, intrauterine hormone-releasing system, 
vasectomy or intrauterine device. Adequate methods of 
contraception are provided as examples. Other acceptable and 
effective methods of birth control are also permitted. 
A FCBP is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 24 consecutive months. 
I 10. 
Voluntary written informed consent before performance of any 
study-related procedure not part of routine medical care with the 
understanding that consent may be withdrawn by the subject at any 
time without prejudice to future medical care. 
I 11. 
Ability to understand the purpose and risks of the study and provide 
signed and dated informed consent and authorization to use 
protected health information (in accordance with national privacy 
regulations). 
Exclusion criteria: 
E 01. 
Patients treated with any anti-CD38 agent. 
E 02. 
Patients with disease measurable only by serum free light chain 
analysis. 
E 03. 
Diagnosed or treated for another malignancy within 5 years prior to 
enrollment, with the exception of complete resection of basal cell 
carcinoma or squamous cell carcinoma of the skin, an in situ 
malignancy, or low-risk prostate cancer after curative therapy. 
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E 04. 
Prior anticancer therapy (chemotherapy, targeted agents, 
immunotherapy) within 21 days prior to the first drug infusion unless 
otherwise specified below, 
• 
Alkylating agents (eg, Melphalan) within 28 days prior to the first 
dose of IMP. 
• 
Steroids treatment (eg, prednisone >10 mg/day orally or equivalent 
except patients being Treated for adrenal insufficiency/replacement 
therapy or Treated for inhalation corticosteroids) within 14 days 
prior to the first dose of IMP. 
• 
Participated in another clinical trial within 30 days prior to the first 
dose of IMP. 
E 05. 
Patients treated with systemic radiation therapy within 4 weeks prior 
to the first dose of IMP or Localized radiation therapy within 1 week 
prior to the first dose of IMP. 
E 06. 
Major surgical procedure within 4 weeks prior to the first dose of 
IMP. 
E 07. 
Patients with laboratory values of:: 
• 
Absolute neutrophil count (ANC) <1,000 cells/μl (1.0 x 109/L) 
 (G-CSF cannot be used within the previous 7 days of the laboratory 
test. Pegylated G-CSF cannot be used within the previous 3 weeks 
of the laboratory test.) 
• 
Platelet count <50,000/μL (without platelet transfusion during the 
7 days previous to the laboratory test). 
• 
Hemoglobin <8.0 g/dL  
(patients may receive red blood cell transfusion) 
• 
AST or ALT >3.0 x upper limit of normal [ULN] 
• 
Total bilirubin >2.0 x ULN 
• 
Estimating glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
using revised equation for eGFR in Japanese. 
• 
Serum calcium (corrected for albumin) level >ULN 
(treatment of hypercalcemia is allowed and subject may be enrolled 
if hypercalcemia returns to normal with standard treatment) 
E 08. 
Any toxicity Grade ≥2 (excluding alopecia, neutropenia or 
neuropathy) related to any prior anti-cancer therapy according to the 
NCI CTCAE version 4.03. 
E 09. 
Neuropathy Grade ≥3 or painful peripheral neuropathy Grade ≥2 
E 10. 
History of significant cardiovascular disease unless the disease 
within the past 6 months is well-controlled.  
Significant cardiac diseases include, 
• 
Second/third degree atrioventricular block 
• 
Significant ischemic heart disease 
• 
QTc interval >450 msec at baseline (read by local cardiologist) 
• 
Poorly controlled hypertension 
• 
Congestive heart failure of NYHA Class III or worse (marked 
limitation of physical activity, comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, dyspnea or anginal 
pain) 
• 
LVEF <45% 
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E 11. 
Previously received an allogenic stem cell transplant. 
E 12. 
Diagnosed Crow-Fukase (POEMS) syndrome or plasma cell 
leukemia. 
E 13. 
Patients with known or suspected amyloidosis. 
E 14. 
Patients with Waldenstrom’s macroglobulinemia or Multiple 
myeloma IgM subtype. 
E 15. 
Patients with active infection requiring systemic antibiotics, antivirals 
or antifungals within 2 weeks prior to the first dose of IMP (except 
when used for chronic prophylaxis). 
E 16. 
Known human immunodeficiency virus (HIV) or active hepatitis B or 
C viral infection. 
E 17. 
Serious psychiatric illness, active alcoholism, or drug addiction that 
may hinder or confuse follow-up evaluation. 
E 18. 
Any medical conditions that, in the Investigator’s opinion, would 
impose excessive risk to the patient (eg, poorly controlled diabetes 
or poorly controlled hypotension). 
E 19. 
Hypersensitivity or history of intolerance to  boron or mannitol, 
sucrose, histidine (as base and hydrochloride salt) and polysorbate 
80 or any of the components of study therapy that are not amenable 
to pre-medication with steroids and H2 blockers or would prohibit 
further treatment with these agents. 
E 20. 
Female subjects who are pregnant or lactating. 
If a female who stopped lactating before entering in the study, the 
female must stop lactating from the day of the first IMP 
administration until 6 months after the last administration of the IMP. 
E 21. 
Any subject who, in the judgment of the Investigator, is likely to be 
noncompliant during the study, or unable to cooperate because of a 
language problem or poor mental development. 
E 22. 
Any subject who cannot be contacted in case of emergency. 
E 23. 
Any subject who is the Investigator or any sub-investigator, research 
assistant, pharmacist, study coordinator, or other staff thereof, 
directly involved in conducting the study. 
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. 
Total expected number of patients 
Phase I part: 6 to 12 evaluable patients 
Phase II part: Approximately 30 patients 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
Isatuximab 
The drug product (isatuximab) is presented as a concentrate for solution for 
infusion in vials containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM 
histidine, 10 % (w/v) sucrose, 0.02 % (w/v) polysorbate 80, pH 6.0 buffer. 
It is supplied for parenteral administration as a sterile, non-pyrogenic, 
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. 
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The pH of the solution is 6.0 (5.7-6.3). The solution contains the following 
excipients: water for injection, 10% sucrose, 20 mM histidine (as base and 
hydrochloride salt) and 0.02% polysorbate 80. 
Route(s) of administration 
Intravenous infusion. The appropriate volume of isatuximab will be diluted in 
an infusion bag of 0.9% sodium chloride solution or 5% dextrose solution. 
Dose regimen 
Phase I part 
• 
Cohort 1:  
1/2 of global maximum administrated dose defined in TED10893  
(ie. 10 mg/kg QW in Cycle 1 (4 weeks) followed by 10 mg/kg Q2W 
in subsequent cycles.) 
• 
Cohort 2:  
Global recommended dose defined in TED10893 
(ie. 20 mg/kg QW in Cycle 1 (4 weeks) followed by 20 mg/kg Q2W 
in subsequent cycles.) 
Phase II part 
• 
Recommended dose defined in Phase I part 
ENDPOINT(S) 
 
Primary endpoint: 
Phase I part 
The safety of Isatuximab will be evaluated using DLT criteria described as 
follows during the Cycle 1. 
The NCI CTCAE version 4.03 will be used to assess the severity of AE and 
serious adverse events (SAE). The DLTs will be determined by the Study 
Committee. 
Hematologic DLTs are defined as any of the following, attributed to 
isatuximab: 
• 
Grade 4 neutropenia lasting for ≥5 days. 
• 
Grade 3 to 4 neutropenia complicated by fever or Microbiologically 
or radiographically documented infection. 
• 
Grade 4 thrombocytopenia lasting for ≥5 days. 
• 
Thrombocytopenia if required platelet transfusion. 
• 
Treatment delay >14 days due to hematologic toxicity. 
Non-hematologic DLTs are defined as any of the following, attributed to 
isatuximab: 
• 
Grade ≥3 non-hematological AE, excluding Grade 3 fatigue,  
Grade 3 to 4 electrolyte abnormalities, Grade 3 
nausea/vomiting/diarrhea if responsive to optimal medical 
management within 48 hours or allergic reaction/ hypersensitivity 
attributed to isatuximab. 
• 
AE that requires treatment delay for >14 days. 
• 
Grade 3 neuropathy will not be considered as a DLT if the patient 
began therapy with Grade 2 neuropathy at baseline. 
Any other toxicity that the Investigator and the sponsor deem to be dose 
limiting, regardless of the grade, may also be considered as DLT. 
Before starting Cohort 2 and Phase II part, all safety data, and the reported 
potential DLTs will be reviewed to determine their relationship to the IMP. 
Starting Cohort 2 or Phase II part decisions will be based on the assessment 
of IMP related DLTs by the Study Committee.  
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Dose escalation will be stopped if ≥33% (≥2 in up to 6 patients) of patients 
experienced an IMP related DLT observed during the first cycles of treatment 
(4 weeks), according to the definition of MAD. 
Phase II part 
ORR is defined as the proportion of patients with stringent complete response 
(sCR), complete response (CR), very good partial response (VGPR), and 
partial response (PR) based on responses as assessed by the Independent 
Adjudication Committee (IAC) using the International Myeloma Working 
Group (IMWG) Uniform Response Criteria. 
Response evaluation will include: 
• 
M-protein quantification (serum and 24-hr urine) 
• 
Serum free light chain levels 
• 
Bone marrow aspiration and/ or biopsy  
• 
CT/MRI scan of plasmacytoma 
• 
Bone skeletal survey 
• 
Corrected serum calcium 
 
Secondary endpoint: 
Safety profile of isatuximab in terms of treatment-emergent adverse events/ 
serious adverse events (TEAE/SAE) and changes in laboratory parameters, 
vital signs, ECGs and assessment of physical examination. 
Assessment of efficacy: 
Efficacy will be determined using IMWG defined response criteria. Efficacy 
parameters will include Overall Response Rate (ORR), Clinical Benefit Rate 
(CBR), Overall Survival (OS), Progression Free Survival (PFS), Duration Of 
Response (DOR) and Time To Progression (TTP). 
PK assessments: 
• 
Concentration observed at the end of an intravenous (IV) infusion 
(Ceoi) 
• 
Maximum observed concentration (Cmax) 
• 
Time to reach the maximum concentration (Tmax) 
• 
Concentrations just before drug infusion (Ctrough) 
• 
AUC over the dosing interval (AUC1week) 
CD38 receptor density assessment: 
• 
CD38 receptor density from baseline bone marrow aspirates. 
Immune response: 
• 
Level of Anti -drug antibodies (ADA).  
Results of additional procedures performed as part of standard of care to 
assess the current disease status may also be collected. 
 
Exploratory Endpoints: 
• 
MRD by sequencing will be assessed in patients achieving a CR. 
• 
Bone marrow samples will be analyzed for multiple myeloma 
molecular subtype (by cytogenetics/ FISH). 
• 
Blood samples will be analyzed for immune genetic determinants 
(including FcγR polymorphisms, HLA and KIR genotypes). 
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• 
Immune phenotype (such as B-cell, T-cell, and NK-cell subsets) in 
bone marrow and peripheral blood will be analyzed. 
• 
Blood samples will be analyzed for soluble factors including CD38. 
Additional molecular 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. 
ASSESSMENT SCHEDULE 
Assessment schedule will include the following (please see Study 
Flowcharts and PK flowcharts for additional details): 
Safety evaluation  
• 
DLT evaluation (Phase I part only) 
• 
AEs according to the NCI-CTC v. 4.03 grading scale 
• 
Vital signs 
• 
ECOG performance status 
• 
12 lead Electrocardiogram (ECG)  
• 
2-D Echocardiogram or Multigated Acquisition (MUGA) scan 
• 
Chest X-ray 
• 
Laboratory safety results (blood, urine) 
• 
Level of ADA 
Pharmacokinetic evaluation  
• 
PK samples will be collected per PK Study Flowcharts. 
Efficacy evaluation  
• 
M-protein quantification (serum and/or 24-hour urine, protein 
electrophoresis), immunofixation and serum FLC levels. 
• 
Serum β2-microglobulin, quantitative immunoglobulins and serum 
calcium. 
• 
Bone skeletal survey, computed tomography (CT) scan or magnetic 
resonance imaging (MRI) as clinically indicated 
• 
Radiologic imaging (CT/MRI scan) of plasmacytoma. 
• 
Survival status 
Biomarkers/ exploratory evaluation  
• 
Bone marrow aspiration and/or biopsy for minimal residual disease 
(MRD). 
• 
CD38 receptor density on plasma cells in bone marrow. 
• 
Soluble CD38 in plasma. 
• 
Cytogenetics/FISH: Probes for fluorescence in situ hybridization 
(FISH) analysis include, at minimum t(4;14), t(14;16) and del(17p). 
• 
Immune genetic determinants: includes Killer cell Ig-like receptors 
(KIR), HLA Typing and FcγR genes. 
• 
Immune phenotyping (peripheral blood and bone marrow samples). 
STATISTICAL CONSIDERATIONS 
 
Determination of the sample size  
Phase I Part 
The Phase I part of this study aims to determine the safety and tolerability of 
Isatuximab. It is anticipated that up to 6 to 12 evaluable patients will be 
enrolled. Patient(s) non evaluable for DLT will be replaced. 
 
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Phase II Part 
The phase II part of the study aims to evaluate 33-36 patients which include 
the subjects in Phase I part at the recommended dose level. Given an 
assumed true ORR of 28%, the null hypothesis ORR ≤10% will be rejected 
using an exact binomial test at a one-sided alpha of 0.025 with at least 80% 
power. 
Analysis populations 
For both Phase I and Phase II parts of the study, the all treated/safety 
population will include all patients who have given their informed consent and 
who have received at least one dose (even incomplete) of Isatuximab. This 
population is the primary population for the analyses of efficacy and safety 
parameters. All analyses using this population will be based on the dose level 
actually received. In the Phase I part, the DLT evaluable population is the 
subset of patients from the all treated population who have completed the first 
cycle which consists of 4 administrations of the IMP, or they discontinued the 
IMP before completion of Cycle 1 for a DLT. The dose escalation will be 
determined on the DLT evaluable population. 
The pharmacokinetic population is the subset of patients from the all treated 
population who have a PK parameter. 
The activity/efficacy population is the subset of patients from the all treated 
population who have evaluable data for exploratory analysis. 
General statistical approach 
Basically, data from initial dose level and recommended dose level will be 
analyzed and reported separately. Only the efficacy evaluated in Phase I 
Cohort 2 and Phase II part is combined for recommended dose level. The 
separate tables will be presented by phase (when appropriate) unless 
otherwise noted. 
Analysis of safety endpoints: 
IMP related DLTs will be assessed and analyzed on DLT evaluable 
population. 
The same analysis below using all treated/safety population will be applied in 
Phase I and Phase II part. 
The treatment emergent adverse events (TEAEs) will be coded according to 
Medical Dictionary for Regulatory Affairs (MedDRA). Adverse events and 
laboratory abnormalities will be graded according to the NCI-CTCAE v. 4.03. 
Number (%) of patients experiencing treatment-emergent adverse events by 
primary system organ class and preferred term will be summarized by CTCAE 
grade (all grades and Grade ≥3) for the safety population. The same table will 
be prepared for drug related TEAEs, TEAEs leading to treatment 
discontinuation, serious TEAEs, TEAEs with fatal outcome, and drug-related 
SAEs occurred during the post treatment dosing period.  
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 safety population. 
The descriptive statistics of all vital signs’ variable will be calculated. 
Analysis of pharmacokinetic and immune response endpoints: 
The same analysis will be applied in Phase I and Phase II part. 
Pharmacokinetic and immune response endpoints and CD38 receptor density 
will be assessed and analyzed on PK population or activity/efficacy 
population. 
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Pharmacokinetics parameters will be summarized with descriptive statistics 
(mean, geometric mean, median, standard deviation, coefficient of variation, 
minimum and maximum). 
Immune response, pharmacodynamics marker results will be descriptively 
summarized and tabulated.  
Analysis of efficacy endpoints: 
Best overall response will be listed along with relevant patient/disease 
characteristics as well as the secondary efficacy endpoints. 
Primary analysis: 
Analysis of efficacy endpoint will be performed on all patients who received at 
least one of the recommended dose across Phase I and II part: 
ORR and a 95% two-sided confidence interval will be computed using 
Clopper-Pearson method. For recommended dose level, the null hypothesis 
that the true response rate (ORR) is <10% will be tested using a one-sided 
exact binomial test with a significance level of 0.025. 
Secondary analysis: 
The CBR will be analyzed using the same method as the primary efficacy 
analysis of ORR. 
DOR, TTP, PFS and OS will be analyzed using Kaplan-Meier methods. 
Analysis of the other exploratory endpoints: 
The same analysis will be applied in Phase I and Phase II part. 
The exploratory endpoints and the relationship to clinical outcomes will be 
analyzed with exploratory manner. 
Planned database lock date: 
The first cutoff date for the database lock is planned at approximately 
4 months after last patient first dosed. 
The second cutoff date for the database lock is planned at approximately 
20 months after last patient first dosed. 
DURATION OF STUDY PERIOD (per 
patient)  
The study duration for an individual patient will include a screening period for 
inclusion of up to 21 days, the treatment period consisting of 28 day cycles 
and a follow-up period. Treatment with isatuximab may continue until disease 
progression, unacceptable adverse event or other reason for discontinuation. 
After study treatment discontinuation, an end of treatment (EoT) visit will be 
done at 30 days to assess safety and ADA, and at 60 days for ADA. If the 
ADA is positive or the sample is inconclusive at Day 60 then ADA will be 
repeated every month (±7 Days) until ADA is negative. Survival status will be 
collected every 3 months until death or second cutoff date, whichever comes 
first. 
Patients with PR or better who come off treatment for reasons other than 
progression of disease will be followed for disease assessment every 4 weeks 
until progression or initiation of subsequent therapy, the second analysis 
cutoff date, whichever comes first. 
For all patients, any study treatment-related adverse events, and all serious 
adverse events (regardless of their causal relationship to study treatment) 
ongoing at the time of study treatment discontinuation will be followed during 
the follow-up period until resolution or stabilization. 
 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
Figure 1 - Study Design of TED14095  
 
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1.2 
TREATMENT SCHEMA  
Figure 2 - Treatment schema of TED14095  
 
 
(IC: Informed Consent form signed, R: Registration, DLT: Dose Limiting Toxicity, EoT: End of Treatment, FUV: Follow-up Visit) 
 
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1.4 
STUDY FLOWCHART - PHASE I PART  
Phase I Part 
Screening/  
Baseline 2 
Cycle 1 3 
Subsequent Cycles 3, 36 
End-of-Treatment 
Follow-up 
Evaluation 1 
D-21 to D-1 
D1 
D2 
D3 
D4 
D84 
D154 
D224 
D14 
D154 
30 days (+/- 7 days) after 
last IMP administration 
60 days (+/- 7 days) after 
last IMP administration 
and subsequent follow-up 
Eligibility criteria & 
Informed consent5 
X 
 
 
 
 
 
 
 
Cycle 2 
only5 
 
 
 
Demography & Medical/surgical & 
Disease History 6 
X 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 7 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
 
Patient Registration 
 
X8 
 
 
 
 
 
 
 
 
 
 
Isatuximab Administration 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Isatuximab Safety Labs 9 
 
(X) 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
Cytokines  
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 10 
X 
X 
 
 
 
X 
X 
X 
X 
Cycle 2,3 only 
X 
 
Performance Status (ECOG) 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs (HR, Temperature, RR, 
BP) 11 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG,  
2D Echocardiogram or MUGA 12 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 13 
X 
X14 
 
 
 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry 15 
X 
X14 
 
 
 
X 
X 
X 
X 
X 
X 
 
Coagulation (PT/INR, aPTT) 16 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 17 
X 
X14 
 
 
 
 
X 
 
X 
X 
X 
 
Pregnancy Test 18 
(Within 7 days prior to Day 1) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
HIV-Ab, HBs-Ag, HBc-Ab, HBs-Ab 
HCV-Ab Tests 19 
X 
 
 
 
 
 
 
 
 
 
 
 
Myeloma-specific Lab Tests 21 
X 
X14 
 
 
 
 
 
 
X 
 
X 
(X) 23 
Extramedullary Disease 22 
X 
 
 
 
 
 
 
 
(Every 12 weeks) 
(X) 
(Every 12 weeks)23 
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Phase I Part 
Screening/  
Baseline 2 
Cycle 1 3 
Subsequent Cycles 3, 36 
End-of-Treatment 
Follow-up 
Evaluation 1 
D-21 to D-1 
D1 
D2 
D3 
D4 
D84 
D154 
D224 
D14 
D154 
30 days (+/- 7 days) after 
last IMP administration 
60 days (+/- 7 days) after 
last IMP administration 
and subsequent follow-up 
Skeletal Survey  
and Chest X-ray  24 
X 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab PK plasma samples 
(See PK flow chart) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (ADA) 25 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
Soluble CD38 (PB) 26 
 
X 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or 
Biopsy 27 
X 
(If CR is suspected) 
 
 
MRD assessment (BM) 28 
X 
(If CR is suspected) 
 
 
CD38 Receptor Density (BM)  
29 
X 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics/ FISH (BM) 30 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune phenotyping (BM) 31 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune phenotyping (PB)32 
 
X 
 
 
 
 
 
 
X 
(C3 only) 
 
X 
 
Immune genetic determinants 
(PB) 33 
 
X 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
X34 
New Anticancer Therapy 
 
 
X 
AE/ SAE Reporting 35  
Continuously throughout the study period 
Prior/ Concomitant Medication 
Continuously throughout the study period 
(PB): Peripheral Blood sample, (BM): Bone Marrow sample 
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1.5 
STUDY FLOWCHART - PHASE II PART  
Phase II Part 
Screening/  
Baseline 2 
Cycle 1 3 
Subsequent Cycles 3, 36 
End-of-Treatment 
Follow-up 
Evaluation 1 
D-21 to D-1 
D1 
D2 
D3 
D4 
D84 
D154 
D224 
D14 
D154 
30 days (+/- 7 days) after 
last IMP administration 
60 days (+/- 7 days) after 
last IMP administration 
and subsequent follow-up  
Eligibility criteria & 
Informed consent5 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography & Medical/surgical & 
Disease History 6 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient Registration 
 
X8 
 
 
 
 
 
 
 
 
 
 
Isatuximab Administration 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Isatuximab Safety Labs 9 
 
(X) 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
Physical Examination 10 
X 
X 
 
 
 
X 
X 
X 
X 
Cycle 2,3 only 
X 
 
Performance Status (ECOG) 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs (HR, Temperature, RR, 
BP)  11 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG,  
2D Echocardiogram or MUGA 12 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 13 
X 
X14 
 
 
 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry 15 
X 
X14 
 
 
 
X 
X 
X 
X 
X 
X 
 
Coagulation (PT/INR, aPTT) 16 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 17 
X 
X14 
 
 
 
 
X 
 
X 
X 
X 
 
Pregnancy Test 18 
(Within 7 days prior to Day 1) 
X 
 
 
 
 
 
 
 
X 
 
X 
 
HIV-Ab, HBs-Ag, HBc-Ab, HBs-Ab 
HCV-Ab Tests 19 
X 
 
 
 
 
 
 
 
X20 
 
 
Myeloma-specific Lab Tests 21 
X 
X14 
 
 
 
 
 
 
X 
 
X 
(X) 23  
Extramedullary Disease 22 
X 
 
 
 
 
 
 
 
(Every 12 weeks) 
(X) 
(Every 12 weeks) 23  
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Phase II Part 
Screening/  
Baseline 2 
Cycle 1 3 
Subsequent Cycles 3, 36 
End-of-Treatment 
Follow-up 
Evaluation 1 
D-21 to D-1 
D1 
D2 
D3 
D4 
D84 
D154 
D224 
D14 
D154 
30 days (+/- 7 days) after 
last IMP administration 
60 days (+/- 7 days) after 
last IMP administration 
and subsequent follow-up  
Skeletal Survey  
and Chest X-ray  24 
X 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab PK plasma samples 
(See PK flow chart) 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (ADA) 25 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
Soluble CD38 26 
 
X 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration and/or 
Biopsy 27 
X 
(If CR is suspected) 
 
 
MRD assessment (BM)  28 
X 
(If CR is suspected) 
 
 
CD38 Receptor Density (BM) 
29
X 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics/FISH (BM) 30 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune phenotyping (BM)31 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune phenotyping (PB) 32 
 
X 
 
 
 
 
 
 
X 
(C3 only) 
 
X 
 
Immune genetic determinants 
(PB) 33 
 
X 
 
 
 
 
 
 
 
 
 
 
Survival Status 
 
 
X34 
New Anticancer Therapy 
 
 
X 
AE/ SAE Reporting 35  
Continuously throughout the study period 
Prior/ Concomitant Medication 
Continuously throughout the study period 
(PB): Peripheral Blood sample, (BM): Bone Marrow sample 
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1.6 
FOOTNOTES FOR STUDY FLOWCHARTS  
1. 
Evaluation: Assessments to be performed prior to study drug administration unless otherwise indicated. Results should be reviewed by the Investigator. 
2. 
If the patient cannot be registered within 21 days of informed consent, the same patient may be re-screened after discussion with the sponsor, provided that there are no persisting safety 
concerns for patient’s study participation. The informed consent form will have to be re-signed by the re-screened patient before starting re-screening procedures. New patient number 
will be given for the re-screened patients. 
3. 
Cycle: A cycle is 28 days.  
4. 
Allowance for Day 8, Day15 and Day 22 at first cycle is +/- 2 days. Allowance for Day 1 and Day15 at subsequent cycles are +/- 3 days. 
5. 
The ICF should be signed before any study-related procedures or tests are initiated.  
All patients who participated in Phase I part and is going to continue study treatment after completing Cycle 1 must sign a second ICF before commencing IMP administration in Cycle 2 
Day1.  
6. 
Demography: Includes date of birth, gender and race.  
Medical/Surgical History: Includes relevant history of previous/associated pathologies other than multiple myeloma. 
Disease History: Includes date of initial diagnosis of symptomatic MM, subtype, stage, previous anti-MM therapy (drug name by line of therapy, start and end date of administration, 
reason for discontinuation, best response and date of progression/relapse), disease status at inclusion (refractory to last IMiD or  PI included therapy). In addition, results of additional 
procedures (such as karyotype, FISH, etc) performed as part of standard of care to assess the current disease status may also be collected. A patient card will be provided to the patient 
indicating he/she is receiving an anti-CD38 treatment and the site will notify its blood bank that the patient is receiving an anti-CD38 treatment. 
7. 
Hospitalization: Day 1 through the entire day of the 3rd infusion (Day 15) hospitalization is recommended. Hospitalization will be expanded to the entire first cycle of the study 
treatment (ie. DLT observation period), if the investigator and the study committee judged appropriate. 
8. 
Registration process can be completed in Day -1 however all eligibility criteria should be re-confirmed by investigators in Day 1 before IMP administration. 
9. 
Isatuximab Safety Labs: Should a isatuximab infusion associated reaction of Grade ≥2 occur, additional blood sampling during the AE is required for analysis of markers of potential 
tumor lysis syndrome (uric acid, lactate dehydrogenase [LDH], BUN, creatinine, potassium, phosphate, ionized or corrected calcium). 
10. Physical Examination: Consists of examination of major body systems including neurological, digestive, extramedullary myeloma localizations, respiratory, hepatomegaly, 
splenomegaly, lymphadenopathy. Only clinically relevant findings will be reported in the electronic case report form (e-CRF) as AEs.  
11. Vital Signs: Heart rate (HR), temperature, respiratory rate (RR), blood pressure (BP) to be taken pre-infusion, mid-infusion (when half the volume is administered), and end-infusion on 
days of investigational medicinal product (IMP) administration. If the infusion rate changes because of an infusion-associated reaction, vital signs should be monitored every hour and at 
the end of the infusion. 
12. 12-Lead ECG, 2-D Echocardiogram or Multigated Acquisition (MUGA): To be performed at screening and then as clinically indicated (the same methods must be used throughout the 
study). LVEF need to be checked for eligibility. 
13. Hematology includes: Hemoglobin, hematocrit, RBC, WBC with differential, Mean Corpuscular Volume (MCV) and platelet counts. To be done at screening, then prior to pre-
medication and IMP administration on Day 1, Day 8, Day 15 and Day 22 of Cycle 1 and on Day 1 and Day 15 of every subsequent cycle, at the EoT visit and as clinically indicated. If 
Grade 4 neutropenia, assess ANC every 2-3 days until ANC ≥0.5 x 109/L and at least weekly thereafter until ANC ≥1.0 x 109/L. Perform direct and indirect coombs tests prior to the first 
IMP administration.  
14. Not required to be repeated prior to Day 1 Cycle 1 if the screening labs were performed within 3 days prior to first IMP administration. 
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15. Serum chemistry includes: SGOT (AST), SGPT (ALT), bilirubin (total and direct), alkaline phosphatase, lactate dehydrogenase (LDH), fasting glucose, sodium, potassium, magnesium, 
chloride, calcium, corrected serum calcium, phosphate, uric acid, blood urea nitrogen (BUN), serum creatinine and eGFR (Revised equations for eGFR in Japanese), albumin and total 
protein. To be done at screening, then prior to pre-medication and IMP administration on Day 1, Day 8, Day 15 and Day 22 of Cycle 1 and on Day 1 and Day 15 of every subsequent 
cycle, at the EoT visit and as clinically indicated. 
16. Coagulation: To be done at screening and then as clinically indicated. Coagulation includes: Prothrombin time (PT) or international normalized ratio (INR) and activated partial 
thromboplastin time (aPTT). 
17. Urinalysis includes: blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrites and specific gravity. To be done at baseline, on Day 1 and Day 15 of each cycle, EoT, and if 
clinically indicated. Quantitative urinalysis will be needed if hematuria is observed or clinically indicated. 
18. Pregnancy Test: Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to first IMP administration and at the EoT visit. Urine test can be 
used at Day 1 of each subsequent cycle. 
19. HBc-Ab, HBs-Ab test: If HBc-Ab and/or HBs-Ab positive at baseline, Hepatitis B Virus (HBV)-DNA test is required prior to registration. If history of HBV infection is suspected, 
monitoring of HBV-DNA is recommended on Day 1 of each cycle, EoT and if clinically indicated.  
20. Once at any time if HBV status unknown before treatment started and to be repeated if clinically indicated. 
21. Myeloma-specific Lab Tests: serum electrophoresis, immunoglobulin assay, corrected serum calcium and 24-hour urine collection for Bence Jones protein to be performed at baseline 
prior to administration, prior to each cycle thereafter and at time of study discontinuation (if last tests were >4 weeks). Serum β2 microglobulin to be performed at baseline prior to 
administration, EoT and if clinically indicated. Immunofixation and free light chain tests to be performed at baseline prior to administration, EOT, if CR is suspected and if clinically 
indicated. 
Bone marrow aspiration to be performed to confirm a CR and as clinically indicated. In case of dry-tap, bone marrow biopsy to be performed to confirm CR. Once CR is confirmed at a 
given time point, a consecutive assessment for immunofixation and free light chain is required. 
22. Extramedullary Disease: Baseline to be performed within 21 days prior to study drug administration. If extramedullary disease present at baseline, to be performed approximately every 
12 weeks (eg. at Cycle 4, 7, 10). To be performed upon clinical suspicion of progressive disease. This may include computerized tomography (CT) or magnetic resonance imaging (MRI) 
scan of the abdomen/pelvis, CT or x-ray of the chest, ultrasound of the liver/spleen or abdomen. May be omitted at End of Treatment if conducted within 12 weeks. All imaging will be 
sent to a central imaging lab. 
23. Disease assessments during follow-up period are only required for patients with PR or better who have discontinued study treatment for reasons other than disease progression and have 
not yet started treatment with another anti-cancer therapy. Patients will be followed every 4 weeks for progression during this period. Disease assessments required every 4 weeks is 
myeloma-specific lab tests. Extramedullary disease assessment is required approximately every 12 weeks or upon clinical suspicion of progressive disease. All imaging will be sent to a 
central imaging lab. A bone marrow aspiration and/or biopsy, skeletal survey are only required if clinically indicated to confirm response or progression according to IMWG criteria. 
Disease assessments not required once patient starts treatment with another anti-cancer therapy. 
24. Skeletal survey and chest X-ray: X-ray to be performed at screening on all patients (the same methods must be used throughout the study). Repeat skeletal surveys are only required as 
clinically indicated. All imaging will be sent to a central imaging lab. 
X-ray skeletal survey should include radiographs of the following: lateral skull; Postero-Anterior (PA) chest; Antero-Posterior(AP) and lateral cervical spine; AP and lateral thoracic 
spine; AP and lateral lumbar spine; AP pelvis; AP upper extremities, shoulder to elbow, bilateral; and AP lower extremities, hip to knee, bilateral. 
Chest X ray: To be performed at screening for assessment of pulmonary disease condition and then as clinically indicated. 
25. ADA (Anti-Drug Antibodies): To be performed on Day 1, Day 8, Day 15, Day 22 of Cycle 1 and Day 1 of cycle up to 10 cycles prior to each IMP administration, at the EoT visit and at 
60 days (± 7 days) after last IMP administration. At 60 days, if patient is positive for ADA or the sample is inconclusive, additional ADA samples are required every 30 days (± 7 days) 
until sample is negative. If ADA is positive at Cycle 10, one additional sampling for ADA evaluation should be collected 3 months later. No further ADA will be collected, even if the 3-
month sample is positive. 
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26. Peripheral blood to be collected on Day 1 of Cycle 1 prior to IMP administration for soluble CD38 analysis. 
27. Bone Marrow Aspiration and/or biopsy: Bone marrow aspiration (BMA) to be collected at screening/baseline. In case of dry-tap, bone marrow biopsy to be performed. Repeat bone 
marrow aspiration and/or biopsy if complete response (CR) is suspected to confirm achievement of response. 
28. MRD Assessment: Bone marrow aspiration and/or biopsy to be collected at screening/baseline. Repeat bone marrow aspiration and/or biopsy if CR is suspected. 
29. CD38 Receptor Density in bone marrow: Bone marrow aspiration to be performed prior to study drug administration at screening/baseline. See PK flowchart. 
30. Cytogenetics/ FISH: Bone marrow aspiration and/or biopsy to be performed prior to study drug administration at screening/ baseline for fluorescence in situ hybridization (FISH) 
analysis. Probes include those to detect del(17p), t(4;14) and t(14;16).  
31. Immune phenotyping (BM): Bone marrow aspiration and/or biopsy to be performed at baseline/screening prior to IMP administration. 
32. Immune phenotyping (peripheral blood): To be performed at Day 1 of Cycle 1, Day 1 of Cycle 3 prior to IMP administration and at the EoT visit. Immune phenotyping in bone marrow 
will be performed by bone marrow sample obtained at the screening/ baseline period. 
33. Immune genetic determinants (peripheral blood): includes Killer cell Ig-like receptors (KIR), HLA Typing and FcγR genes. To be performed at Day 1 of Cycle 1 prior to IMP 
administration. 
34. Survival status: Patients will also be followed for survival status approximately every 3 months (± 14 days) from the date of last IMP administration until death or second cutoff date, 
whichever comes first. Every effort will be made to follow all patients. If survival follow-up is missed and is not obtained at the time of the scheduled interval, it should be obtained 
immediately. For subsequent survival follow-up, the patient should be contacted at the original scheduled survival follow-up interval. If the patient is unable to visit the clinical center, 
the follow-up may be done via phone from the Investigator or designee to the patient or the patient's caregiver or a family member. 
35. Adverse Event/Serious AE Reporting: All AEs, including events of new onset as well as worsening of baseline signs and symptoms are to be reported from the signing of the informed 
consent to 30 days following the last administration of study treatment. After the 30 day follow-up all ongoing related AEs, ongoing SAE/AESIs regardless of relationship and new 
related AE/SAE/AESIs are to be followed to resolution or stabilization. 
36. Post second analysis cut-off period, only AE/SAE reporting will be collected 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL NO. 05 ....................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
DOCUMENT HISTORY ................................................................................................................................... 3 
AMENDED PROTOCOL 05 (15-JUL-2020) ................................................................................................... 4 
OVERALL RATIONALE FOR THE AMENDMENT ......................................................................................... 4 
1 
FLOW CHARTS ............................................................................................................................. 15 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 15 
1.2 
TREATMENT SCHEMA ................................................................................................................. 16 
1.3 
DESIGN DIAGRAM........................................................................................................................ 17 
1.4 
STUDY FLOWCHART - PHASE I PART ....................................................................................... 19 
1.5 
STUDY FLOWCHART - PHASE II PART ...................................................................................... 21 
1.6 
FOOTNOTES FOR STUDY FLOWCHARTS ................................................................................ 23 
1.7 
PK FLOW CHART - PHASE I PART ............................................................................................. 26 
1.8 
PK FLOW CHART - PHASE II PART ............................................................................................ 27 
2 
TABLE OF CONTENTS ................................................................................................................ 28 
2.1 
LIST OF TABLES ........................................................................................................................... 34 
2.2 
LIST OF FIGURES ......................................................................................................................... 34 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 35 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 37 
4.1 
INTRODUCTION ............................................................................................................................ 37 
4.2 
MULTIPLE MYELOMA................................................................................................................... 37 
4.3 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ............................................... 38 
4.3.1 
Clinical Experience with Single-agent of Isatuximab ..................................................................... 38 
4.4 
RATIONALE ................................................................................................................................... 42 
4.4.1 
Study Rationale .............................................................................................................................. 42 
4.4.2 
Study Design Rationale ................................................................................................................. 42 
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4.4.3 
Rationale of Dose and Regimen .................................................................................................... 42 
5 
STUDY OBJECTIVES ................................................................................................................... 44 
5.1 
PRIMARY OBJECTIVE(S): ............................................................................................................ 44 
5.2 
SECONDARY OBJECTIVE(S): ..................................................................................................... 44 
5.3 
EXPLORATORY OBJECTIVE(S): ................................................................................................. 44 
6 
STUDY DESIGN ............................................................................................................................ 45 
6.1 
DESCRIPTION OF THE PROTOCOL ........................................................................................... 45 
6.2 
STARTING DOSE AND DOSE ESCALATION DESIGN ............................................................... 45 
6.2.1 
Dose Levels ................................................................................................................................... 45 
6.2.2 
Dose Escalation ............................................................................................................................. 45 
6.3 
MAXIMUM ADMINISTERED DOSE / MAXIMUM TOLERATED DOSE ........................................ 46 
6.4 
RETREATMENT OF PATIENTS ................................................................................................... 47 
6.5 
DOSE DELAYS/ MODIFICATIONS ............................................................................................... 47 
6.6 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS: ..................................................... 47 
6.6.1 
Management of Potential Infusion Associated Reactions (IARs) .................................................. 47 
6.6.2 
Management of Potential Tumor Lysis Syndrome ......................................................................... 49 
6.6.3 
Guidance in case of hepatitis B reactivation occurring under study treatment .............................. 49 
6.7 
DURATION OF STUDY PARTICIPATION .................................................................................... 50 
6.7.1 
Duration of Study Participation for Each Patient ............................................................................ 50 
6.7.2 
Determination of End of Clinical Trial (all patients) ........................................................................ 50 
6.8 
INTERIM ANALYSIS ...................................................................................................................... 50 
6.9 
STUDY COMMITTEE .................................................................................................................... 51 
6.9.1 
Study Committee ............................................................................................................................ 51 
6.9.2 
Independent Adjudication Committee ............................................................................................ 51 
7 
SELECTION OF PATIENTS .......................................................................................................... 52 
7.1 
NUMBER OF PATIENTS ............................................................................................................... 52 
7.2 
INCLUSION CRITERIA .................................................................................................................. 52 
7.3 
EXCLUSION CRITERIA ................................................................................................................ 53 
8 
STUDY TREATMENTS ................................................................................................................. 56 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 56 
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8.1.1 
Pharmaceutical Form ..................................................................................................................... 56 
8.1.2 
Dose of Drug per Administration .................................................................................................... 56 
8.1.3 
Preparation, Reconstitution and Administration of isatuximab ...................................................... 57 
8.1.4 
Stability under Light........................................................................................................................ 57 
8.1.5 
Packaging and Labeling ................................................................................................................. 57 
8.1.6 
Storage Conditions and Shelf Life ................................................................................................. 57 
8.2 
METHOD OF REGISTERING PATIENTS TO THE STUDY ......................................................... 58 
8.3 
PRE-MEDICATION ........................................................................................................................ 58 
8.4 
RESPONSIBILITIES ...................................................................................................................... 59 
8.4.1 
Treatment Accountability and Compliance .................................................................................... 59 
8.4.2 
Return and/or Destruction of IMPs ................................................................................................. 59 
8.5 
CONCOMITANT TREATMENT ..................................................................................................... 60 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 61 
9.1 
SAFETY ......................................................................................................................................... 61 
9.1.1 
Dose-limiting Toxicities in Phase I part .......................................................................................... 61 
9.1.2 
Adverse Events .............................................................................................................................. 62 
9.1.3 
Laboratory Safety Variables ........................................................................................................... 62 
9.1.4 
Clinical Examinations ..................................................................................................................... 62 
9.1.5 
Vital Signs ...................................................................................................................................... 62 
9.1.6 
ECG ............................................................................................................................................... 63 
9.1.7 
Chest X-Ray ................................................................................................................................... 63 
9.1.8 
Immunogenicity .............................................................................................................................. 63 
9.1.9 
Other Clinical Assessments ........................................................................................................... 63 
9.2 
PHARMACOKINETIC EVALUATION ............................................................................................ 63 
9.2.1 
Sampling Time and Sample Blood Volume ................................................................................... 63 
9.2.2 
Pharmacokinetic Sample Handling Procedure .............................................................................. 64 
9.2.3 
Bioanalytical Method ...................................................................................................................... 64 
9.2.4 
Pharmacokinetic Parameters ......................................................................................................... 64 
9.3 
EFFICACY ..................................................................................................................................... 65 
9.3.1 
Criteria for Response ..................................................................................................................... 65 
9.4 
SPECIFIC ASSESSMENTS .......................................................................................................... 66 
9.4.1 
CD38 Receptor Density Assessment............................................................................................. 66 
9.4.2 
Minimal Residual Disease Assessment ......................................................................................... 67 
9.4.3 
Exploratory Biomarker Studies ...................................................................................................... 67 
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10 
PATIENT SAFETY ......................................................................................................................... 69 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ..................................................................... 69 
10.2 
SAFETY INSTRUCTIONS ............................................................................................................. 69 
10.3 
ADVERSE EVENTS MONITORING .............................................................................................. 69 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT .................................. 69 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 70 
10.5.1 
Adverse Events .............................................................................................................................. 70 
10.5.2 
Serious Adverse Events, Adverse Events of Special Interest, Pregnancy and Symptomatic 
Overdose ........................................................................................................................................ 70 
10.5.3 
Follow-up ........................................................................................................................................ 71 
10.5.4 
Treatment discontinuation due to non-serious adverse event ....................................................... 71 
10.5.5 
Adverse Event of Special Interest .................................................................................................. 71 
10.5.6 
Pregnancy ...................................................................................................................................... 72 
10.5.7 
Symptomatic Overdose .................................................................................................................. 72 
10.5.8 
Laboratory Abnormalities ............................................................................................................... 72 
10.6 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 73 
11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ...................................... 74 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) ................................................................................................................................. 74 
11.1.1 
List of Criteria for Permanent Treatment Discontinuation .............................................................. 74 
11.1.2 
Handling of Patients after Permanent Treatment Discontinuation ................................................. 75 
11.1.3 
Temporary Treatment Discontinuation with Investigational Medicinal Product(s) ......................... 75 
11.2 
REPLACEMENT OF PATIENTS ................................................................................................... 75 
12 
STUDY PROCEDURES ................................................................................................................ 76 
12.1 
VISIT SCHEDULE .......................................................................................................................... 76 
12.2 
BASELINE EVALUATION .............................................................................................................. 76 
12.3 
DURING THE TREATMENT PERIOD ........................................................................................... 78 
12.3.1 
Day 1 of Each Cycle....................................................................................................................... 78 
12.3.2 
Day 2, 3, 4 of Cycle 1 of Phase I part ............................................................................................ 80 
12.3.3 
Day 8 and Day 22 of Cycle 1 ......................................................................................................... 80 
12.3.4 
Day 15 of Each Cycle..................................................................................................................... 81 
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12.4 
END OF TREATMENT VISIT (TO BE PERFORMED 30 DAYS (+/- 7 DAYS) AFTER THE 
LAST ADMINISTRATION OF THE INVESTIGATION MEDICINAL PRODUCT) .......................... 82 
12.5 
FOLLOW-UP VISIT (TO BE PERFORMED 60 DAYS (+/- 7 DAYS) AFTER THE LAST 
ADMINISTRATION OF THE INVESTIGATION MEDICINAL PRODUCT) .................................... 83 
12.6 
PERIOD POST 60 DAYS FOLLOW-UP PERIOD ......................................................................... 84 
12.7 
POST SECOND ANALYSIS CUT-OFF PERIOD .......................................................................... 85 
13 
STATISTICAL CONSIDERATIONS .............................................................................................. 86 
13.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 86 
13.2 
PATIENT DESCRIPTION .............................................................................................................. 86 
13.2.1 
Disposition of Patients ................................................................................................................... 86 
13.2.2 
Protocol Deviations ........................................................................................................................ 86 
13.3 
ANALYSIS POPULATIONS ........................................................................................................... 86 
13.3.1 
All-treated/safety Population .......................................................................................................... 86 
13.3.2 
Patients Evaluable for DLT Assessment........................................................................................ 87 
13.3.3 
Pharmacokinetic Population .......................................................................................................... 87 
13.3.4 
Activity/efficacy Population ............................................................................................................ 87 
13.4 
STATISTICAL METHODS ............................................................................................................. 87 
13.4.1 
Demographics and Baseline Characteristics ................................................................................. 87 
13.4.2 
Extent of Investigational Medicinal Product Exposure ................................................................... 88 
13.4.3 
Prior/concomitant Medication/therapy............................................................................................ 88 
13.4.4 
Analyses of Safety Data ................................................................................................................. 89 
13.4.4.1 Dose-limiting toxicities.................................................................................................................... 89 
13.4.4.2 Analyses of adverse events ........................................................................................................... 89 
13.4.4.3 Deaths ............................................................................................................................................ 90 
13.4.4.4 Clinical laboratory evaluations ....................................................................................................... 90 
13.4.4.5 Vital signs ....................................................................................................................................... 91 
13.4.4.6 Analyses of other safety variables ................................................................................................. 91 
13.4.5 
Analyses of Pharmacokinetic Variables ......................................................................................... 91 
13.4.6 
Analysis of Anti-drug Antibody ....................................................................................................... 91 
13.4.7 
Analysis of CD38 Receptor Density ............................................................................................... 91 
13.4.8 
Analyses of Efficacy Variables ....................................................................................................... 91 
13.4.8.1 Efficacy endpoints for Phase I part of the study ............................................................................ 92 
13.4.8.2 Analysis of primary efficacy endpoint for Phase I (Recommended dose level) and Phase II 
part of the study ............................................................................................................................. 92 
13.4.8.3 Analysis of secondary efficacy endpoint for Phase II part of the study ......................................... 92 
13.4.8.4 Analysis of the other exploratory endpoints ................................................................................... 92 
13.5 
INTERIM ANALYSIS ...................................................................................................................... 92 
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14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 93 
14.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 93 
14.2 
INFORMED CONSENT ................................................................................................................. 93 
14.3 
INSTITUTIONAL REVIEW BOARD ............................................................................................... 93 
15 
STUDY MONITORING................................................................................................................... 95 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 95 
15.2 
RESPONSIBILITIES OF SPONSOR ............................................................................................. 95 
15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 96 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS ........... 96 
15.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 96 
16 
ADDITIONAL REQUIREMENTS ................................................................................................... 97 
16.1 
CURRICULUM VITAE.................................................................................................................... 97 
16.2 
RECORD RETENTION IN STUDY SITES(S) ............................................................................... 97 
16.3 
CONFIDENTIALITY ....................................................................................................................... 97 
16.4 
PROPERTY RIGHTS ..................................................................................................................... 98 
16.5 
DATA PROTECTION ..................................................................................................................... 98 
16.6 
INSURANCE COMPENSATION .................................................................................................... 98 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 99 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 99 
16.8.1 
By the Sponsor ............................................................................................................................... 99 
16.8.2 
By the Investigator ....................................................................................................................... 100 
16.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 100 
16.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 100 
17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 101 
18 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 102 
19 
APPENDICES .............................................................................................................................. 104 
APPENDIX A 
ECOG PERFORMANCE STATUS SCALE ....................................................................... 104 
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APPENDIX B 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 105 
APPENDIX C 
IMWG RESPONSE CRITERIA.......................................................................................... 106 
APPENDIX D 
DEFINITION OF LINE OF THERAPY ............................................................................... 108 
APPENDIX E 
DEFINITION OF RELAPSED AND REFRACTORY MYELOMA ...................................... 109 
APPENDIX F 
STAGING CRITERIA ......................................................................................................... 110 
APPENDIX G 
DEFINITIONS OF INFUSION ASSOCIATED REACTIONS (IARS) ................................. 111 
APPENDIX H 
REVISED EQUATIONS FOR ESTIMATED GFR IN JAPANESE ..................................... 112 
APPENDIX I 
CD38 BLOOD TEST INTERFERENCE GUIDELINE AABB2016 ....................................... 113 
APPENDIX J 
PROTOCOL AMENDMENT HISTORY .............................................................................. 117 
  
2.1 
LIST OF TABLES  
Table 1 - TED10893 – Phase 2 (Stage 1): Summary of TEAEs with an incidence ≥20% by system organ 
class and preferred term  – All treated population (extracted from the database as of 6-Nov-2015) ........... 40 
Table 2 - Dose escalation decision rule ........................................................................................................ 46 
Table 3 - Infusion associated reactions management ................................................................................... 48 
Table 4 - Tumor lysis syndrome management .............................................................................................. 49 
Table 5 - Summary of handling procedures .................................................................................................. 64 
Table 6 - Bioanalytical method for isatuximab in plasma .............................................................................. 64 
Table 7 - List of pharmacokinetic parameters and definitions ....................................................................... 65 
Table 8 - Sample handling procedure and Analytical method for CD38 receptor density assessment ........ 67 
Table 9 - International Myeloma Working Group Response Criteria .......................................................... 106 
Table 10 - Additional response criteria for specific disease states ............................................................. 107 
Table 11 - Staging criteria for multiple myeloma ......................................................................................... 110 
Table 12 - Types of infusion associated reactionsa .................................................................................... 111 
Table 13 - Symptoms typically associated with infusion associated reactionsa ......................................... 111 
 
2.2 
LIST OF FIGURES  
Figure 1 - Study Design of TED14095 .......................................................................................................... 15 
Figure 2 - Treatment schema of TED14095 .................................................................................................. 16 
Figure 3 - Dose escalation design for Cohort 1 (Initial dose level) ............................................................... 17 
Figure 4 - Dose escalation design for Cohort 2 (global recommended dose level) ...................................... 18 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
ADCC: 
anti-body-dependent cell mediated cytotoxicity 
ADI: 
actual dose intensity 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALL: 
acute lymphocytic leukemia 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
ASCT: 
autologous stem cell transplantation 
AST: 
aspartate aminotransferase 
BUN: 
blood urea nitrogen 
CBR: 
clinical benefit rate 
CD: 
cluster of differentiation 
CDC: 
complement-dependent cytotoxicity 
CLL: 
chronic lymphocytic leukemia 
CR: 
complete response 
CRF: 
case report form 
DLTs: 
dose limiting toxicities 
DOR: 
duration of response 
DRF: 
discrepancy resolution form 
ECOG: 
eastern cooperative oncology group 
eGFR: 
estimated glomerular filtration rate 
EoT: 
end of treatment 
FCBP: 
female patients of childbearing potential 
FcγR: 
crystalizable fragment gamma receptor 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
GCP: 
Good Clinical Practice 
G-CSF: 
granulocyte colony stimulating factor 
HBc-Ab: 
Hepatitis B Core Antibody 
HBs-Ab: 
Hepatitis B Surface Antibody 
HBs-Ag: 
Hepatitis B Surface Antigen 
HBV: 
Hepatitis B Virus 
HIV: 
human immunodeficiency virus 
HLA: 
human leukocyte antigens 
IAC: 
independent adjudication committee 
IARs: 
infusion associated reactions 
ICH: 
International Conference on Harmonisation 
IMiDs: 
immunomodulatory drugs 
IMP: 
investigational medicinal product 
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IMWG: 
international myeloma working group 
INR: 
international normalized ratio 
IRB: 
institutional review board 
Islands: 
Isatuximab singLe agent study in japanese relapsed AND refractory multiple 
myeloma patientS 
IV: 
intravenous 
kDa: 
kilodalton 
KIR: 
killer cell Ig-like receptors 
LDH: 
lactate dehydrogenase 
mAb: 
monoclonal antibody 
MAD: 
maximum administrated dose 
MCV: 
mean corpuscular volume 
MFC: 
multiparametric flow cytometry 
MHLW: 
Ministry of Health, Labour and Welfare 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
MUGA: 
multigated acquisition 
NAD: 
nicotinamide adenine dinucleotide 
NCI CTCAE: 
national cancer institute common terminology criteria for adverse events 
ORR: 
overall response rate 
OS: 
overall survival 
PD: 
progressive disease 
PFS: 
progression free survival 
PIs: 
proteasome inhibitors 
PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred terms 
Q2W: 
once every other week 
QTc: 
QT interval corrected for heart rate 
QW: 
once every week 
RD: 
receptor density 
RDI: 
relative dose intensity 
SAE: 
serious adverse event 
sCR: 
stringent complete response 
SD: 
stable disease 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reactions 
TEAE: 
treatment emergent adverse event 
TLS: 
tumor lysis syndrome 
TTP: 
time to progression 
ULN: 
upper limit of normal 
VGPR: 
very good partial response 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
CD38 is a type II glycosylated 45 kilodalton (kDa) 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. 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 co-receptors (2). CD38 is also an ecto-enzyme catalyzing the synthesis 
and hydrolysis of cyclic adenosine-diphosphate-ribose (cADPR) from nicotinamide adenine 
dinucleotide (NAD+) to ADP-ribose (3). These reaction products are implicated in calcium 
mobilization and intracellular signaling. 
The expression of CD38 in healthy humans can be detected on 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-
lymphocyte, T-lymphocyte and myeloid origin. Moreover, CD38 was identified as a negative 
prognostic marker in some hematological malignancies, such as CLL. The expression of CD38 is 
especially notable in multiple myeloma (MM) as >98% of patients are positive for this protein (4, 
5). The strong and uniform expression of CD38 on malignant clonal MM cells contrasts with the 
restricted expression pattern on normal cells suggesting this antigen may be useful for specific 
targeting of tumor cells. 
Isatuximab (SAR650984) is a naked IgG1 kappa monoclonal antibody (mAb) directed against 
CD38, a receptor antigen expressed on hematopoietic cells. Isatuximab is produced in a 
mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology.  The 
monoclonal anti-body isatuximab has 4 modes of action to kill target cells: 
• 
Anti-body-dependent cell mediated cytotoxicity (ADCC) 
• 
Complement-dependent cytotoxicity (CDC) 
• 
Pro-apoptotic activity 
• 
Inhibition of CD38 enzyme activity (6) 
In preclinical tumor models in mice, it was active as a single agent and in combination with 
reference treatments, on several CD38-positive tumors in multiple hematological malignancies, 
including multiple myeloma (MM), non-Hodgkin’s-lymphoma and leukemia.  
4.2 
MULTIPLE MYELOMA  
MM is a malignant plasma cell disease that is characterized by clonal proliferation of plasma cells 
in the bone marrow and the production of excessive amounts of a monoclonal immunoglobulin 
(usually of the IgG or IgA type or free urinary light chain [paraprotein, M protein or M-
component])(7). It is a disease predominantly associated with advancing age with 88.8% of 
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patients aged 60 years or older and only about 0.4% of cases are diagnosed in individuals under 
the age of 40. In 2011, there were an estimated 6,860 new cases of MM in Japan, with incidence 
rates 5.493 cases per 100,000 males and 5.249 cases per 100,000 females, but the incidence of 
MM for aged 85 years or older was 35.428 cases per 100,000 males and 19.316 cases per 100,000 
females. In year 2003-2005, the 5-year survival rate was 32.6% [number of sample: 1,156] (8).  
Patients with MM can experience bone pain, bone fractures, fatigue, anemia, infections, 
hypercalcemia, and kidney problems (9). The disease course for MM varies with the 
aggressiveness of the disease and related prognostic factors. Median survival is approximately 3 
to 5 years; however, some patients can live longer than 10 years (10). Treatment options and 
survival are based on the patient’s disease characteristics including disease stage, b-2 
microglobulin level. Patients presenting with symptomatic active disease and in otherwise good 
physical health can receive consolidation therapy with autologous stem cell transplantation 
(ASCT) to enhance remission duration. However, all patients with MM will receive some form of 
induction chemotherapy to achieve cytoreduction, and to induce remission of their disease. The 
type of induction therapy will vary greatly depending on age, disease status and presence of other 
comorbidities. The newer agents including bortezomib (Velcade®), and lenalidomide (Revlimid®) 
are currently used most often as these agents demonstrate higher RRs and lower toxicity (9). 
Without autologous transplantation, patients typically have remission durations of between 18 and 
36 months. Invariably, relapse occurs and additional therapy is needed. Treatment for relapse 
and/or refractory disease is often referred to as salvage therapy. 
At present, the therapeutic options for relapsed and refractory patients, defined as disease that is 
nonresponsive to salvage therapy or progresses within 60 days of the last therapy in patients who 
achieved an MR or better to any previous therapy is very limited (11). In view of the lack of 
effective therapeutic options in relapsed and refractory myeloma patients, additional effective 
therapies are urgently needed. 
TED14095 Study was designed to assess isatuximab monotherapy in Japanese patients with 
relapsed and refractory multiple myeloma who had exhausted available options, including a PI 
and an IMiD.  
4.3 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT  
Isatuximab is a naked IgG1 monoclonal antibody directed against CD38, and has 3 modes of 
action to kill target cells such as ADCC, CDC, pro-apoptotic activity and Inhibition of CD38 
enzyme activity. 
More detail information on compound description, previous human experience, pharmacology, 
toxicology and Pharmacokinetic Profile is provided in Investigators Brochure. 
4.3.1 Clinical Experience with Single-agent of Isatuximab  
Isatuximab is being tested both as a single agent and in combination with MM backbones in late 
and early lines. The TED10893 study, a first-in-human Phase I/II dose escalation safety and 
pharmacokinetic (PK) study of multiple IV administrations of isatuximab in patients with selected 
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CD38+ hematological malignancies including MM is ongoing. The Phase I dose escalation part 
has been completed back on 2014 and have explored several dose levels ranging from 0.0001 
mg/kg up to 20 mg/kg Q2W or weekly. The first results of the Phase I art were presented at 
ASH2013 and ASCO 2014 (12, 13) and are described in the IB. In the latest part of the Phase I, 
three cohorts were enrolled sequentially, an expansion cohort of RRMM patients that were treated 
at 10 mg/kg (N= 19), a high risk cohort (based on clinical GEP and cytogenetics characteristics 
(n= 18 at 10 mg/kg) and a third cohort of 6 patients treated at 20 mg/kg QW. The ORR for 
patients treated at 10 mg/kg is 28% (n= 25, 6 from the dose escalation part and 19 from the 
expansion cohort). Amongst the patients treated in the high risk cohort the ORR was 22%. For the 
cohort of patients treated at 20 mg/kg QW the observed ORR was 29%. 
The Phase II Stage 1 was designed to evaluate 4 cohorts with respectively the following doses and 
schedules: 3 mg/kg Q2W (N= 23), 10 mg/kg Q2W (N= 24), 10 mg/kg Q2W for 8 weeks followed 
by Q4W (N= 25), and 20 mg/kg Q2W for 4 weeks followed by Q2W (N= 25) in order to identify 
the dose and schedule of administration and move forward to the Stage 2. This first stage has been 
completed and the results are described below. 
A summary of the most frequent TEAEs is presented in Table 1. Overall, isatuximab appeared to 
be well tolerated at all dose levels tested. At doses ≥10mg/kg, preliminary data show no difference 
in terms of type, incidence and severity of TEAEs. Infusion associated reactions occurred in 
approximately half of patients and were of Grade 1/2 for all patients except for 2 patients treated 
at 10mg/kg Q2W.Preliminary efficacy data show a dose response effect between 3 mg/kg Q2W 
(ORR<10%) and the doses ≥10 mg/kg (ORR ≥20 %). At doses ≥10 mg/kg, response rate was 
ranging from 20% to 29%, without clear dose response between the 10 mg/kg and the 20 mg/kg 
arms. 
 
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Table 1 - TED10893 – Phase 2 (Stage 1): Summary of TEAEs with an incidence ≥20% by system organ class and preferred term  
– All treated population (extracted from the database as of 6-Nov-2015)  
Primary SOC 
 
3mg/kg Q2W 
(N=23) 
 
 
10mg/kg Q2W 
(N=24) 
 
 
10mg/kg 
Q2W/Q4W 
(N=25) 
 
 
20mg/kg 
QW/Q2W 
(N=25) 
 
Preferred Term 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
Any TEAEs 
22 (95.7%) 
16 (69.6%) 
23 (95.8%) 
16 (66.7%) 
25 (100%) 
14 (56.0%) 
24 (96.0%) 
11 (44.0%) 
 
 
 
 
 
 
 
 
 
Infections and infestations 
12 (52.2%) 
7 (30.4%) 
12 (50.0%) 
6 (25.0%) 
15 (60.0%) 
2 (8.0%) 
12 (48.0%) 
4 (16.0%) 
Upper respiratory tract infection 
5 (21.7%) 
2 (8.7%) 
3 (12.5%) 
0 
7 (28.0%) 
0 
3 (12.0%) 
0 
 
 
 
 
 
 
 
 
 
Blood and lymphatic system disorders 
10 (43.5%) 
9 (39.1%) 
4 (16.7%) 
3 (12.5%) 
6 (24.0%) 
6 (24.0%) 
10 (40.0%) 
6 (24.0%) 
Anemia 
9 (39.1%) 
8 (34.8%) 
2 (8.3%) 
1 (4.2%) 
5 (20.0%) 
5 (20.0%) 
7 (28.0%) 
4 (16.0%) 
Thrombocyto-penia 
4 (17.4%) 
4 (17.4%) 
0 
0 
0 
0 
8 (32.0%) 
5 (20.0%) 
 
 
 
 
 
 
 
 
 
Nervous system disorders 
8 (34.8%) 
1 (4.3%) 
9 (37.5%) 
1 (4.2%) 
11 (44.0%) 
0 
7 (28.0%) 
1 (4.0%) 
Headache 
4 (17.4%) 
0 
3 (12.5%) 
0 
8 (32.0%) 
0 
3 (12.0%) 
0 
 
 
 
 
 
 
 
 
 
Respiratory, thoracic and mediastinal disorders 
13 (56.5%) 
4 (17.4%) 
15 (62.5%) 
3 (12.5%) 
18 (72.0%) 
1 (4.0%) 
17 (68.0%) 
1 (4.0%) 
Dyspnea 
7 (30.4%) 
1 (4.3%) 
5 (20.8%) 
1 (4.2%) 
7 (28.0%) 
1 (4.0%) 
6 (24.0%) 
0 
Cough 
3 (13.0%) 
1 (4.3%) 
8 (33.3%) 
0 
5 (20.0%) 
0 
7 (28.0%) 
0 
 
 
 
 
 
 
 
 
 
Gastrointestinal disorders 
14 (60.9%) 
2 (8.7%) 
11 (45.8%) 
0 
17 (68.0%) 
2 (8.0%) 
11 (44.0%) 
1 (4.0%) 
Nausea 
7 (30.4%) 
0 
8 (33.3%) 
0 
11 (44.0%) 
0 
6 (24.0%) 
0 
Diarrhea 
5 (21.7%) 
0 
5 (20.8%) 
0 
8 (32.0%) 
1 (4.0%) 
5 (20.0%) 
0 
Vomiting 
1 (4.3%) 
0 
3 (12.5%) 
0 
6 (24.0%) 
0 
6 (24.0%) 
0 
Constipation 
7 (30.4%) 
0 
2 (8.3%) 
0 
2 (8.0%) 
0 
1 (4.0%) 
0 
 
 
 
 
 
 
 
 
 
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Primary SOC 
 
3mg/kg Q2W 
(N=23) 
 
 
10mg/kg Q2W 
(N=24) 
 
 
10mg/kg 
Q2W/Q4W 
(N=25) 
 
 
20mg/kg 
QW/Q2W 
(N=25) 
 
Preferred Term 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
All Grades 
Grade≥3 
Musculoskeletal and connective tissue disorders 
10 (43.5%) 
2 (8.7%) 
14 (58.3%) 
2 (8.3%) 
10 (40.0%) 
2 (8.0%) 
9 (36.0%) 
2 (8.0%) 
Back pain 
3 (13.0%) 
1 (4.3%) 
7 (29.2%) 
2 (8.3%) 
3 (12.0%) 
1 (4.0%) 
4 (16.0%) 
1 (4.0%) 
 
 
 
 
 
 
 
 
 
General disorders and administration site conditions 
15 (65.2%) 
3 (13.0%) 
15 (62.5%) 
0 
17 (68.0%) 
2 (8.0%) 
16 (64.0%) 
1 (4.0%) 
Fatigue 
5 (21.7%) 
0 
5 (20.8%) 
0 
11 (44.0%) 
0 
8 (32.0%) 
0 
Chills 
4 (17.4%) 
0 
5 (20.8%) 
0 
6 (24.0%) 
0 
3 (12.0%) 
0 
Chest discomfort 
1 (4.3%) 
0 
4 (16.7%) 
0 
3 (12.0%) 
0 
6 (24.0%) 
0 
 
 
 
 
 
 
 
 
 
Injury, poisoning and procedural complications 
10 (43.5%) 
0 
14 (58.3%) 
2 (8.3%) 
17 (68.0%) 
2 (8.0%) 
13 (52.0%) 
1 (4.0%) 
Infusion related reaction 
9 (39.1%) 
0 
11 (45.8%) 
2 (8.3%) 
13 (52.0%) 
0 
13 (52.0%) 
0 
Only PTs with ≥20% in all grades in at least one group are presented with SOC.  
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4.4 
RATIONALE  
4.4.1 Study Rationale  
Standard therapy of MM includes proteasome inhibitors (PIs) such as bortezomib, 
immunomodulatory drugs (IMiDs) such as lenalidomide, pomalidomide and thalidomide, and 
chemotherapy such as melphalan. While these agents have improved survival in MM, invariably 
resistance becomes problematic and patients succumb from their illness. Therefore, there is 
significant unmet medical need for the late line MM. 
The CD38 antigen was identified as a negative prognostic marker of clinical importance in some 
hematological malignancies. As a consequence, monoclonal antibodies to CD38 have the 
potential to treat a variety of hematological indications including MM, B-cell NHL, chronic 
lymphocytic leukemia (CLL), acute myeloid leukemia and B-cell ALL. Plasma cells have a high 
concentration of CD38 receptors and could be an ideal target for this novel therapeutic agent. 
Myeloma cells have a slower growth fraction than other hematologic malignancies and may be 
more suitable for antibody therapy. 
4.4.2 Study Design Rationale  
This is an open-label, single arm, local multi-center study will be conducted in 2 parts, Phase I 
and Phase II. 
The study comprises a Phase I part using traditional “3+3” design and a Phase II part at the 
recommended dose level. The Phase I part is designed to confirm the safety in Japanese at two 
doses where isatuximab has been already tested and deemed safe in global study, TED10893. 
Dose escalation or move to the Phase II part will be confirmed by the study committee after the 
first cycle of isatuximab of the last patient in the current cohort.  
Phase II part will further evaluate the efficacy and safety of isatuximab at the recommended dose 
level defined in Phase I part. The single-arm design for the Phase II part is suitable for early 
evaluation of the efficacy and safety isatuximab in consideration of the target patients in this 
study. Also, since there is limited drug approved in patients with relapsed and refractory multiple 
myeloma who have previously received an IMiD and a proteasome inhibitor. According to the 
recent approved drug for the relapsed and refractory patients, an overall response rate target of 20 
- 30% is considered to be clinically meaningful. (14) 
4.4.3 Rationale of Dose and Regimen  
In the dose escalation phase of study TED10893, isatuximab was administered by IV infusion 
once every 2 weeks at doses initially ranging from 0.0001 to 20 mg/kg and weekly at 10 mg/kg. 
The dose of 10 mg/kg Q2W was selected to be used for the treatment of the two cohorts described 
above (standard and high risk cohorts) based on an analysis of safety, PK and efficacy data. 
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The evaluation of isatuximab PK using both non-compartmental and modeling approaches show 
that there was a high variability of exposure within a given dose level and isatuximab has a 
nonlinear PK behavior with dose increases. Furthermore, the analysis of patients enrolled in the 
standard risk expansion cohort of TED10893 showed that some patients at 10 mg/kg Q2W still 
presented a biphasic elimination profiles. These data suggest that isatuximab exhibits nonlinear 
pharmacokinetics with target-mediated clearance dominating the elimination phase at low 
concentrations (10-20 μg/mL), which leads to low exposure in these patients and overall to a high 
inter-patient variability at this dose and schedule.  
The TED10893 study was subsequently amended in order to explore the administration of 
isatuximab at 20 mg/kg weekly (in the Phase 1 part) and in a schedule consisting of weekly 
dosing for 4 weeks followed by every other week (in the Phase 2 part) and subsequently to 
explore additional doses and schedules of administration. The global recommended dose and 
schedule (see Section 6.2.1) was determined based on the response rate along with safety, PK, 
pharmacodynamics and overall efficacy.  
A preliminary PK/PD analysis to evaluate the relationship between ORR and PK parameters was 
performed using an Emax model with pooled Phase 1 and Phase 2 Stage 1 data.  This analysis 
showed that Ctrough at week 4 (CT4W)) was a significant predictor of ORR. The probability of 
response to treatment increases as CT4W increases up to a plateau. This plateau was reached for 
CT4W values following a weekly administrations at 20 mg/kg, indicating that frequent 
administrations together with a high dose at the first cycle  is needed to optimize the response 
(4 weekly administrations at 20 mg/kg). Based on safety, efficacy and PK/PD modeling and 
simulation, the selected dose and schedule of administrations for TED10893 Phase II Stage 2 
(global recommended dose level) are: 20 mg/kg weekly (QW) for 4 weeks followed by 20 mg/kg 
every 2 weeks (Q2W). 
Therefore, the initial dose level in this study will be 10 mg/kg QW for 4 weeks then 10 mg/kg 
Q2W which is the half of the global recommended dose (20 mg/kg QW for 4 weeks then Q2W), 
which is regarded as reasonably safe and well tolerated. 
All patients will receive pre-medication (Section 8.3) for prophylaxis of infusion associated 
reactions (IARs). 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY OBJECTIVE(S):  
Phase I part 
• 
To evaluate safety and tolerability of isatuximab in Japanese patients with relapsed and 
refractory multiple myeloma. 
Phase II part 
• 
To evaluate efficacy of isatuximab at recommended dose and to further evaluate the 
overall response rate (ORR) of isatuximab in Japanese patients with relapsed and 
refractory multiple myeloma. 
5.2 
SECONDARY OBJECTIVE(S):  
• 
To evaluate the safety including immunogenicity of isatuximab. The severity, frequency 
and incidence of all adverse events will be assessed. 
• 
To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing 
schedule. 
• 
To assess the efficacy using International Myeloma Working Group (IMWG) uniform 
response criteria. 
• 
To assess the relationship between baseline CD38 receptor density on multiple myeloma 
cells and efficacy. 
5.3 
EXPLORATORY OBJECTIVE(S):  
• 
To assess minimal residual disease (MRD) in patients achieving Complete Response (CR) 
and correlate with clinical outcome. 
• 
To investigate the relationship of soluble CD38 and parameters of PK and clinical 
response. 
• 
To investigate the relationship between multiple myeloma molecular subtype (as defined 
by cytogenetics/ FISH) and parameters of clinical response. 
• 
To investigate the relationship between immune genetic determinants, immune phenotype 
and parameters of clinical response. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE PROTOCOL  
This is an open-label, non-randomized, single arm, local multi-center study conducted in 2 parts, 
Phase I and Phase II. 
6.2 
STARTING DOSE AND DOSE ESCALATION DESIGN  
The rationale for selecting the starting dose and the dose escalation design are described in 
Section 4.4. Intra patient dose escalation is not permitted. 
The dose escalation decision will be made based on dose limiting toxicities (DLTs) observed 
during Cycle 1 of the study treatment, and deemed to be related to the investigational medicinal 
product (IMP) in absence of clear evidence to the contrary after validation by the Study 
Committee, and if not related to a disease progression. Cumulative toxicities observed upon 
subsequent administrations should also be considered for the dose escalation process and the dose 
selection decision. The Study Committee role is described in Section 6.9. 
The definitions of DLTs are provided in Section 9.1.1. 
The Phase II part is to commence after the Cohort 2 of Phase I part has completed enrollment and 
DLT evaluation. Patients enrolled in Phase II part will be given the recommended dose 
determined in Phase I part.  
6.2.1 Dose Levels  
• 
Phase I part Cohort 1: 1/2 of global maximum administrated dose defined in TED10893 
(ie. 10 mg/kg QW in Cycle 1 (4 weeks) followed by 10 mg/kg Q2W in subsequent cycles) 
• 
Phase I part Cohort 2: Global recommended dose defined in TED10893 
(ie. 20 mg/kg QW in Cycle 1 (4 weeks) followed by 20 mg/kg Q2W in subsequent cycles) 
• 
Phase II part: Recommended dose level defined in Phase I part 
(10 mg/kg or 20 mg/kg QW in Cycle 1 (4 weeks) followed by Q2W in subsequent cycles) 
No additional or intermediate dose level is planned in this study. Refer to Section 1.2 for the 
treatment schema. 
6.2.2 Dose Escalation  
In each cohort of Phase I part, at least 3 and a maximum of 6 patients will be treated and observed 
for DLT in Cycle 1 (4 weeks). At least 7 calendar days must pass after dosing the first patient 
before dosing the subsequent patients in Cohort 1. The dose escalation rule is described in 
Figure 3 and in below:  
• 
If none of the 3 patients experience a DLT, the Cohort 2 or Phase II part starts. 
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• 
If 1 of the 3 patients experiences a related DLT, up to 3 additional patients are treated at 
the same dose level. 
• 
If 2 or more patients experience a related DLT, the maximum administrated dose (MAD) 
is reached. 
The above plan is summarized hereafter. 
Table 2 - Dose escalation decision rule  
Number of patients with DLT 
observed at each cohort 
Dose escalation decision rule 
DLT in 0/3  
Proceed to the next cohort or phase 
DLT in 1/3  
Enroll 3 additional patients at the same dose level : 
• 
If 0 out of 3 additional patients experienced DLT (ie.1 DLT/6 patients)  
→ proceed  to the next cohort or phase 
• 
If 1 or more of 3 additional patients experienced DLT (ie. ≥2 DLTs/6 
patients)→ Defines MAD and dose escalation is stopped.   
(If only 3 patients were treated at Cohort 1 and ≥2 DLTs/6 patients were 
confirmed in Cohort 2, 3 additional patients may be treated at the Cohort 1 dose 
level upon recommendation from the study committee.) 
DLT in 2/3  
 
Defines MAD and dose escalation is stopped.  
(If only 3 patients were treated at Cohort 1 and ≥2 DLTs/6 patients were 
confirmed in Cohort 2, 3 additional patients may be treated at the Cohort 1 dose 
level upon recommendation from the study committee.) 
DLT evaluation Period:  
First cycle  
 
6.3 
MAXIMUM ADMINISTERED DOSE / MAXIMUM TOLERATED DOSE  
If a DLT in Phase I part at Cycle 1 is observed in at least 2 out of a maximum of 6 treated patients 
(≥33%) at a dose level, there will be no further dose escalation and this dose level will constitute 
the MAD. In this circumstance, the maximum tolerated dose (MTD) is defined as one level lower 
dose of the MAD. 
Although the dose escalation process is guided by the safety evaluation during DLT observation 
period, cumulative or irreversible toxicities observed in subsequent administrations should also be 
considered for the dose escalation and dose selection decisions, upon agreement of the study 
committee. 
In absence of MTD, the tested dose in Cohort 2 will be defined as the recommended dose of 
isatuximab and to be tested in the Phase II part of the study. PK, cumulative safety and efficacy 
data may be used to review the recommended dose level by the study committee as needed. 
Dose and phase escalation algorism are illustrated in Section 1.3. 
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6.4 
RETREATMENT OF PATIENTS  
The patient must have recovered to his/her baseline status or Grade ≤1 for any toxicities before 
initiating the next dose. In those cases of clear clinical benefit, a patient can continue the study 
treatment until disease progression, unacceptable toxicity, or patient’s decision. 
6.5 
DOSE DELAYS/ MODIFICATIONS  
In this study, Cycle 1 consists of 4 isatuximab administrations and consecutive cycles consist of 
2 isatuximab administrations. 
A dose delay of up to 2 weeks is permitted in order for a patient to recover to their baseline status 
(see Section 6.4) or to accommodate scheduling issues (eg, holidays, weather, etc.). In case of a 
delay greater than 2 weeks the patient will be withdrawn from the treatment as per the investigator 
and the Sponsor decision. Exceptions allowed by the investigator and the Sponsor should be 
considered only for patients with clear objective clinical benefit. 
Intra-patient dose and schedule modifications are not allowed. 
6.6 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS:  
6.6.1 Management of Potential Infusion Associated Reactions (IARs)  
Patient(s) should routinely receive pre-medications prior to isatuximab infusion as detailed in 
Section 8.3 to reduce the risk and severity of IARs commonly observed with monoclonal 
antibodies. Infusion associated reactions (NCI-CTCAE, version 4.03 term Infusion related 
reaction), including “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.  
Refer to Appendix G for diagnoses Table 12 and symptoms typical of an infusion associated 
reactionTable 13. 
General guidelines for the management of IARs are provided in Table 3. 
 
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Table 3 - Infusion associated reactions management  
NCI CTCAE v. 4.03 criteria definition 
Recommendation 
Mild 
Grade 1  
Infusion interruption not indicated;  intervention not indicated 
Continuation of isatuximab infusion is 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 hrs.) 
Stop isatuximab infusion; 
Give additional pre-medication with diphenhydramine 25 mg IV 
(or equivalent) and/ or IV methylprednisolone 100 mg (or 
equivalent) as needed. Isatuximab may be resumeda only after 
patient recovery, with slower infusion rate and with close 
monitoring. (ie. infusion may be restarted at one half of the 
original infusion rates.  If symptoms do not recur after 30 minutes, 
the infusion rate may be increased in 50 mg/hour increments 
every 30 minutes, to a maximum of 400 mg/hour). 
Important:  
Additional blood sampling during the AE is required for analysis 
of markers of potential TLS (uric acid, lactate dehydrogenase 
[LDH], BUN, creatinine, potassium, phosphate, ionized or 
corrected calcium).  
Severe or life-threatening 
Grade 3 or 4  
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.  
Life-threatening, consequences; urgent intervention 
indicated. 
Stop isatuximab infusion; 
Give additional medication with diphenhydramine 25 mg IV (or 
equivalent) and/ or IV methylprednisolone 100 mg (or equivalent) 
and/or epinephrine as needed. 
Definitive treatment discontinuation. 
Important:  
Additional blood sampling during the AE is required for analysis 
of markers of potential TLS (uric acid, lactate dehydrogenase 
[LDH], BUN, creatinine, potassium, phosphate, ionized or 
corrected calcium). 
a The infusion should be completed within 16 hours from the end of infusion preparation or a new infusion should be prepared with the 
remaining dose to be administered the same day. 
 
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6.6.2 Management of Potential Tumor Lysis Syndrome  
General guidelines for the management of the tumor lysis syndrome are provided in Table 4. 
Table 4 - Tumor lysis syndrome management  
Symptom 
Recommended Action 
Laboratory Tumor Lysis Syndrome (LTLS): 
• 
≥ 2 simultaneous abnormalities within 3 days prior 
to and up to 7 days after start of treatment 
• 
Uric acid >8 mg/dL (>475.8 μmol/L) 
• 
Potassium >6.0 mmol/L 
• 
Phosphorus >4.5 mg/dL (>1.45 mmol/L) 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L) or ionized 
calcium <1.12 mg/dL (<0.3 mmol/L) a 
 
Clinical TLS (CTLS):  
meeting criteria for LTLS in addition to one 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/hr for 6 hrs. 
• 
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 
• 
Dysrhythmia probably or definitely caused by 
hyperkaliemia 
Omit isatuximab until all serum chemistries have resolved 
Ensure normal hydration; correct laboratory abnormalities, 
fluid overload, electrolyte or acid-based deviations 
Monitor TLS complications including renal functions 
Refer to “serious adverse drug reaction countermeasure 
manual” for TLS treatmentb.  
Reinstitute isatuximab treatment at full doses after resolution 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8x(4-albumin in grams per 
deciliter) 
b Serious adverse drug reaction countermeasure manual for TLS: http://www.mhlw.go.jp/topics/2006/11/dl/tp1122-1e17.pdf 
MHLW site: http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou_iryou/iyakuhin/topics/tp061122-1.html 
6.6.3 Guidance in case of hepatitis B reactivation occurring under study treatment  
Patient still on treatment at the time of amended protocol 05 will be tested for HBV serology and 
HBV viral DNA once at any time if HBV status was unknown before treatment started; test will 
be repeated if clinically indicated.  
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection) 
study treatment will be held and specialist consulted for initiation of anti-viral treatment and 
monitoring of the patient. Resolved infection means previous known history of acute or chronic 
hepatitis B or the presence of total anti-HBc Ab with/without anti-HBs Ab; HBsAg negative; 
undetectable serum HBV DNA; and normal ALT levels. Restart of study treatment should be 
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agreed between the Sponsor, the Investigator and specialist (hepatologist) if infection is 
controlled. ALT and AST will be closely monitored every month up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
6.7 
DURATION OF STUDY PARTICIPATION  
6.7.1 Duration of Study Participation for Each Patient  
The study duration for an individual patient will include a screening period for inclusion of up to 
21 days, the treatment period consisting of 28 day cycles and a follow-up period. Treatment with 
isatuximab may continue until disease progression, unacceptable adverse event or other reason for 
discontinuation. 
After study treatment discontinuation, an end of treatment (EoT) visit will be done at 30 days to 
assess safety and ADA, and at 60 days for ADA. If the ADA is positive or the sample is 
inconclusive at Day 60 then ADA will be repeated every month (±7 Days) until ADA is negative. 
Survival status will be collected approximately every 3 months until death or second cutoff date 
(refer to Section 6.7.2), whichever comes first. 
Patients with PR or better who come off treatment for reasons other than progression of disease 
will be followed for disease assessment every 4 weeks until progression or initiation of 
subsequent therapy, the second analysis cutoff date, whichever comes first. 
For all patients, any study treatment-related adverse events, and all serious adverse events 
(regardless of their causal relationship to study treatment) ongoing at the time of study treatment 
discontinuation will be followed during the follow-up period until resolution or stabilization. 
6.7.2 Determination of End of Clinical Trial (all patients)  
The first analysis cutoff date for the statistical analysis for ORR will be 4 months after the date of 
the first dose of the last patient.  
Second analysis cutoff date for the updated analysis of ORR and final analysis of time to events 
data will be 20 months after the date of the first dose of the last patient. Patients still on treatment 
at time of the second analysis cutoff date and who still continue benefiting from treatment with 
isatuximab will have the option to continue treatment under this protocol. Study will end after the 
completion of follow-up for all patients. 
6.8 
INTERIM ANALYSIS  
No interim analysis is planned. 
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6.9 
STUDY COMMITTEE  
6.9.1 Study Committee  
The Study Committee will be set up to include at least the external medical expert, the Principal 
Investigator of each participating sites in Phase I part and clinical team members from the 
Sponsor (Clinical Study Director and/or Medical Advisor), and ad hoc experts when appropriate. 
The Study Committee will regularly review safety data during the course of the study.  
Confirmations to escalate dose or to initiate Phase II part, in accordance with description in the 
study protocol, will be made with the appropriate data review by the Study Committee at the end 
of Cohort 1 and Cohort 2 of Phase I part. A tracking form with all TEAEs or adverse event page 
and DLT page of the e-CRF will be distributed ahead of time and reviewed. Any of these 
communications will be documented in writing and communicated to all investigators in a timely 
manner. 
6.9.2 Independent Adjudication Committee  
The Independent Adjudication Committee (IAC) will be responsible for objectively assessing 
clinical response as defined by the IMWG response criteria on an ongoing basis in order to 
independently evaluate the drug effect of isatuximab on disease status. 
The IAC will be comprised of multiple independent MM experts. They will be responsible for: 
• 
Objectively assessing clinical response as defined by the IMWG response criteria on an 
ongoing basis in order to independently evaluate the drug effect of isatuximab on disease 
status 
• 
The IAC will determine response using: 
- 
Serum and urine M-protein, free light chains (FLC), bone marrow aspirate/biopsy and 
corrected calcium 
- 
Radiologic results for bone lesions and plasmacytoma assessment 
Detailed guidelines regarding the structure, function and decision-making mechanisms for this 
committee are described in the IAC charter. 
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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
Refer to Section 13.1. 
7.2 
INCLUSION CRITERIA  
I 01.  Males or females, age 20 years or older. 
I 02. Patient must have a known diagnosis of symptomatic multiple myeloma. 
I 03. Patients must have received at least 3 prior lines of therapies which must include treatment 
with an Immunomodulatory Drug (IMiD, eg. Lenalidomide, Pomalidomide or 
Thalidomide) AND a Proteasome Inhibitor (PI, eg. Bortezomib). The patients must have 
received an IMiD and a PI for ≥2 cycles or ≥2 months of treatment. 
OR 
Patients whose disease is double refractory to an IMiD and a PI.  For patients who have 
received more than one type of IMiD and PI, their disease must be refractory to the most 
recent one. The patients must have received an IMiD and a PI for ≥2 cycles or ≥2 months 
of treatment. 
I 04. Subject must have been responsive (ie. Minimal Response [MR] or better) to at least one 
prior line of therapy. 
I 05. Refractory to the most recently received IMiD or PI included therapy (patient must 
progress during or within 60 days of completion of treatment with IMiD or PI).  
I 06. Patients with measurable disease defined as at least one of the followings: 
• 
IgG Type: Serum M-protein ≥1 g/dL (≥10 g/L) 
• 
IgA Type: Serum M-protein ≥0.5 g/dL (≥5 g/L) 
• 
IgD Type: Serum M-protein ≥0.5 g/dL (≥5 g/L) 
• 
Urine M-protein ≥200 mg/24 hours 
I 07. Patients with a Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
I 08. Life expectancy of at least 3 months. 
I 09. Female patients of childbearing potential (FCBP) and male patients with female partners of 
childbearing potential who agreed to avoid pregnancy by using an adequate method of 
contraception for 2 weeks prior to screening, during and 6 months after the last 
administration of the IMP. Acceptable and effective methods of contraception includes 
2 barrier method or 1 barrier method with a spermicide (spermicide is only available for 
purchase with condoms or diaphragm), oral hormonal contraception, intra-uterine 
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hormone-releasing system, vasectomy or intrauterine device. Adequate methods of 
contraception are provided as examples. Other acceptable and effective methods of birth 
control are also permitted. 
A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or 
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
24 consecutive months. 
I 10. Voluntary written informed consent before performance of any study-related procedure not 
part of routine medical care with the understanding that consent may be withdrawn by the 
subject at any time without prejudice to future medical care. 
I 11. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (in accordance with 
national privacy regulations). 
7.3 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the 
following exclusion criteria:  
E 01. Patients treated with any anti-CD38 agent. 
E 02. Patients with disease measurable only by serum free light chain analysis. 
E 03. Diagnosed or treated for another malignancy within 5 years prior to enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the 
skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 
E 04. Prior anticancer therapy (chemotherapy, targeted agents, immunotherapy) within 21 days 
prior to the first drug infusion unless otherwise specified below, 
• 
Alkylating agents (eg, Melphalan) within 28 days prior to the first dose of IMP. 
• 
Steroids treatment (eg, prednisone >10 mg/day orally or equivalent except patients being 
Treated for adrenal insufficiency/replacement therapy or Treated for inhalation 
corticosteroids) within 14 days prior to the first dose of IMP. 
• 
Participated in another clinical trial within 30 days prior to the first dose of IMP. 
E 05. Patients treated with systemic radiation therapy within 4 weeks prior to the first dose of 
IMP 
OR 
Localized radiation therapy within 1 week prior to the first dose of IMP. 
E 06. Major surgical procedure within 4 weeks prior to the first dose of IMP. 
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E 07. Patients with laboratory values of: 
• 
Absolute neutrophil count (ANC) <1,000 cells/μl (1.0 x 109/L) (G-CSF cannot be used 
within the previous 7 days of the laboratory test. Pegylated G-CSF cannot be used within 
the previous 3 weeks of the laboratory test.). 
• 
Platelet count <50,000/µL (without platelet transfusion during the 7 days previous to the 
laboratory test). 
• 
Hemoglobin <8.0 g/dL  
(patients may receive red blood cell transfusion). 
• 
AST or ALT >3.0 x upper limit of normal [ULN]. 
• 
Total bilirubin >2.0 x ULN. 
• 
Estimating glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 using revised equation 
for eGFR in Japanese (see Appendix H). 
• 
Serum calcium (corrected for albumin) level >ULN 
(treatment of hypercalcemia is allowed and subject may be enrolled if hypercalcemia 
returns to normal with standard treatment). 
E 08. Any toxicity Grade ≥2 (excluding alopecia, neutropenia or neuropathy) related to any prior 
anti-cancer therapy according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03. 
E 09. Neuropathy Grade ≥3 or painful peripheral neuropathy Grade ≥2 
E 10.  History of significant cardiovascular disease unless the disease within the past 6 months is 
well-controlled.  
Significant cardiac diseases include, 
• 
Second/third degree atrioventricular block 
• 
Significant ischemic heart disease 
• 
QTc interval >450 msec at baseline (read by local cardiologist) 
• 
Poorly controlled hypertension 
• 
Congestive heart failure of NYHA Class III or worse (marked limitation of physical 
activity comfortable at rest, but less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain) 
• 
LVEF <45% 
Significant ischemic heart disease (eg, angina) and poorly controlled hypertension are 
defined as medical conditions that, in the opinion of the Investigator or Sponsor, may 
interfere with patient’s participation in the study, affect the interpretation of the study 
results, or patient’s safety. 
E 11. Previously received an allogenic stem cell transplant. 
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E 12. Diagnosed Crow-Fukase (POEMS) syndrome  
OR 
plasma cell leukemia. 
E 13.  Patients with known or suspected amyloidosis. 
E 14. Patients with Waldenstrom’s macroglobulinemia 
OR 
Multiple myeloma IgM subtype. 
E 15. Patients with active infection requiring systemic antibiotics, antivirals or antifungals within 
2 weeks prior to the first dose of IMP (except when used for chronic prophylaxis). 
E 16. Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection.  
E 17. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse 
follow-up evaluation. 
E 18. Any medical conditions that, in the Investigator’s opinion, would impose excessive risk to 
the patient (eg, poorly controlled diabetes or poorly controlled hypotension). 
E 19. Hypersensitivity or history of intolerance to  boron or mannitol, sucrose, histidine (as base 
and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that 
are not amenable to pre-medication with steroids and H2 blockers or would prohibit further 
treatment with these agents. 
E 20. Female subjects who are pregnant or lactating.  
If a female who stopped lactating before entering in the study, the female must stop 
lactating from the day of the first IMP administration until 6 months after the last 
administration of the IMP. 
E 21. Any subject who, in the judgment of the Investigator, is likely to be noncompliant during 
the study, or unable to cooperate because of a language problem or poor mental 
development. 
E 22. Any subject who cannot be contacted in case of emergency. 
E 23. Any subject who is the Investigator or any sub-investigator, research assistant, pharmacist, 
study coordinator, or other staff thereof, directly involved in conducting the study. 
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. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
8.1.1 Pharmaceutical Form  
The drug product (isatuximab) is presented as a concentrate for solution for infusion in vials 
containing 20 mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10 % (w/v) sucrose, 
0.02 % (w/v) polysorbate 80, pH 6.0 buffer. 
It is supplied for parenteral administration as a sterile, non-pyrogenic, 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. 
The pH of the solution is 6.0 (5.7-6.3). The solution contains the following excipients: water for 
injection, 10% sucrose, 20 mM histidine (as base and hydrochloride salt) and 0.02% polysorbate 
80. 
For administration to patients, the appropriate volume of isatuximab will be diluted in an infusion 
bag of 0.9% sodium chloride solution or 5% dextrose solution. The final infusion volume 
corresponding to the dose of isatuximab will be administered for 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  
Isatuximab will be administered once every week (QW) in Cycle 1 (4 weeks) followed by once 
every other week (Q2W) in subsequent cycle until unacceptable toxicity, disease progression, 
withdrawal of consent and/or Investigator’s decision (Section 1.2). Cycle N day 1 corresponds to 
cycle N-1 day 29. 
 For dose level and schedule, refer to Section 6.2.1. 
The initial rate of infusion of isatuximab will be 175 mg/hour. 
• 
First infusion:  
Initiate infusion rate at 175 mg/hour. In the absence of infusion associated reaction after 
1 hour of infusion, increase the rate by 50 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour. 
• 
Subsequent infusions:  
Initiate infusion rate at 175 mg/hour. In the absence of infusion associated reaction after 
1 hour of infusion, increase the rate by 100 mg/hour increments every 30 minutes, to a 
maximum of 400 mg/hour. 
 
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recovered, the infusion may be restarted at one half of the original infusion rates. If symptoms do 
not recur after 30 minutes, the infusion rate may be increased in 50 mg/hour increments every 
30 minutes, to a maximum of 400 mg/hour. 
8.1.3 Preparation, Reconstitution and Administration of isatuximab  
Isatuximab concentrate for solution will be diluted in an infusion bag with 0.9% sodium chloride 
solution or 5% dextrose solution to achieve the appropriate drug concentration for infusion. 
Infusion via a central line is preferred if available. 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 (detailed 
above). Prior to dosing, each patient's dose will be individually prepared by the hospital 
pharmacist. 
A 0.20 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 for infusion; if an in-line filter is 
unavailable, a 0.20-micron filter unit may be attached to the administration set before 
administration. 
Detail instruction for dilution of the isatuximab concentrate for solution for infusion is provided in 
a Pharmacy Manual. 
8.1.4 Stability under Light  
No protection from light is required for storage in the infusion bags. 
8.1.5 Packaging and Labeling  
The Investigational Medicinal Product (IMP) is packaged in 30 mL glass vials fitted with 
elastomeric closure. 
The content of the labeling is in accordance with the regulatory specifications and requirements. 
8.1.6 Storage Conditions and Shelf Life  
The IMP is stored at +2°C to +8°C. Storage of IMP should be in a secure area with restricted 
access. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
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8.2 
METHOD OF REGISTERING PATIENTS TO THE STUDY  
At the time of informed consent, the study site will assign each patient a unique patient 
identification number. After obtained the informed consent from the patient, the site should 
inform the registration center (pre-registration). 
The patient number must be used for patient identification on all study-related documents 
(e-CRFs, clinic notes, laboratory samples, CT scans, MRIs, etc). After confirmation of all 
eligibility, the site should inform the registration center (registration). 
The site should inform the registration center at the EoT (30 days [+/- 7 days] after last IMP 
administration) and at the Follow-up (60 days [+/- 7 days] after last IMP administration) as well. 
The above mentioned procedures will be applied to both Phase I part and Phase II part. 
8.3 
PRE-MEDICATION  
Patient(s) should routinely receive pre-medications prior to isatuximab infusion to reduce the risk 
and severity of IARs commonly observed with monoclonal antibodies. The recommended 
pre-medication is: on the day of isatuximab infusion, 100 mg methylprednisolone (or equivalent) 
will be administered via intravenous (IV) or oral (PO) route along with diphenhydramine 50 mg 
IV (or equivalent); ranitidine 50 mg IV (or equivalent) and acetaminophen 650 to 1000 mg PO. 
The pre-medication regimen should be initiated at least 15 minutes (but no longer than 60 
minutes) prior to isatuximab infusion and isatuximab administration is to be initiated as soon as 
the pre-medication regimen is completed. The order of pre-medications should be acetaminophen, 
ranitidine, diphenhydramine, and then methylprednisolone when methylprednisolone is 
administered via IV route. When methylprednisolone is given via PO route, the order of 
pre-medications will be methylprednisolone (PO), acetaminophen (PO), ranitidine (IV), 
diphenhydramine (IV). General guidelines for the management of the IARs are provided in 
Section 6.6.1. If an IAR is observed, patients must also be informed of the potential risk of 
recurrent IARs. 
Patients who do not experience an IAR during the 4 consecutive administrations of isatuximab 
may have the need for subsequent pre-medication reconsidered at the investigator’s discretion in 
consultation with the Sponsor. 
If a subject experiences a Grade 1 to 2 infusion-related AE during infusion, the following can be 
initiated: 
• 
The methylprednisolone 100 mg IV (or equivalent) and diphenhydramine 25 mg IV (or 
equivalent) can be given. 
 
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8.4 
RESPONSIBILITIES  
The Investigator, sub-investigator or the hospital pharmacist allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with the regulatory requirements. 
The IMP will be dispensed in accordance with the Investigator's or sub-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 IMP and eliminate potential hazards. 
Under no circumstances the Investigator will supply IMP to a third party, allows the IMP to be 
used other than as directed by this clinical trial protocol, or disposes of IMP in any other manner. 
8.4.1 Treatment Accountability and Compliance  
Administration of the IMP will be supervised by the Investigator or sub-investigator. 
The person responsible for drug dispensing is required to maintain adequate records of the 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 (PR 
Nr) on the vial must be recorded on the drug accountability form. 
The person responsible for drug administration to the patient will record precisely the date and the 
time of the drug administration to the patient. 
8.4.2 Return and/or Destruction of IMPs  
All used and partially-used IMPs will be destroyed at the study site after an accurate 
accountability has been performed, signed by the Investigator or the pharmacist, and reconciliated 
by the Sponsor monitoring team.  
All unused IMP will be destroyed on site, after final batch accountability has been validated by 
the Sponsor monitoring team representative, according to the standard practices of the site and /or 
to local regulations. The Investigator will not destroy unused IMP unless the Sponsor provides 
written authorization or according to local procedures. 
The destruction is recommended to be performed at site depending on IMP specificities and local 
requirements but IMP can be returned to the Sponsor for destruction. 
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A potential defect in the quality of IMP may be subject to initiation by Sanofi of a recall 
procedure. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
8.5 
CONCOMITANT TREATMENT  
All treatments being taken by the patient 7 days prior to first dose of IMP, at any time during the 
treatment period and up to 30 days after the last dose are regarded as prior and concomitant 
treatments respectively. These will be reported on the appropriate pages of the e-CRF. 
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 IMP, they may 
be given at the discretion of the Investigator and recorded in the e-CRF: 
• 
Palliative radiotherapy may be given for control of pain for palliative intents. Sanofi 
should be notified to obtain approval if palliative radiotherapy is being considered, and 
prior to resuming therapy on the study. The irradiated area should be as small as possible 
and should never involve more than 20% of the bone-marrow in any given 3-week period. 
In all such cases, the possibility of tumor progression should be ruled out by physical and 
radiological assessments of the tumor. 
• 
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 trial and the reason for its administration must be recorded on the e-CRF. 
The following concomitant treatments are not permitted during this study: 
• 
Concurrent treatment with other investigational drugs. 
• 
Concurrent treatment with any other anticancer therapy not specified in this protocol, 
including immunotherapy, hormonal therapy, targeted therapy, steroid therapy or 
biological therapies. 
• 
Prophylactic use of hematopoietic growth factors (eg, Pegylated G-CSF) during the DLT 
observation period (1st Cycle) in Phase I part. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
SAFETY  
The major purpose of the Phase I part is to determine safety and tolerability of isatuximab when 
administrated as an IV infusion to Japanese patients with relapsed and refractory multiple 
myeloma. A secondary objective of the Phase II part is to evaluate the safety of isatuximab when 
administered at recommended dose defined in Phase I part as an IV infusion to Japanese patients 
with relapsed and refractory multiple myeloma.  
The safety profile will be assessed from the findings of physical examination (preferably by the 
same physician), laboratory tests, etc., and will be based on incidence, severity (as graded by the 
NCI CTCAE v. 4.03, see Appendix B), and cumulative nature of AEs as defined in Section 10.4. 
The NCI CTC AE v 4.03(15) can be accessed through the NCI website at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
9.1.1 Dose-limiting Toxicities in Phase I part  
For the purposes of dose escalation and determination of tolerability of recommended dose, only 
DLTs that occur during the first cycle of treatment will be considered for decisions regarding dose 
escalation and phase transition. The standard duration of DLT evaluation period is 28 days 
however treatment delay up to 14 days is allowed in the first cycle. The detailed DLT evaluability 
is defined in Section 13.3.2. 
Hematologic DLTs are defined as any of the following, attributed to isatuximab: 
• 
Grade 4 neutropenia lasting for ≥5 days. 
• 
Grade 3 to 4 neutropenia complicated by fever 
OR 
Microbiologically or radiographically documented infection. 
• 
Grade 4 thrombocytopenia lasting for ≥5 days. 
• 
Thrombocytopenia if required platelet transfusion. 
• 
Treatment delay >14 days due to hematologic toxicity. 
Non-hematologic DLTs are defined as any of the following, attributed to isatuximab: 
• 
Grade ≥3 non-hematological AE, excluding Grade 3 fatigue, Grade 3 to 4 electrolyte 
abnormalities, Grade 3 nausea/vomiting/diarrhea if responsive to optimal medical 
management within 48 hours or allergic reaction/ hypersensitivity attributed to isatuximab. 
• 
AE that requires treatment delay for >14 days. 
• 
Grade 3 neuropathy will not be considered as a DLT if the patient began therapy with 
Grade 2 neuropathy at baseline. 
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Any other toxicity that the Investigator and the sponsor deem to be dose limiting, regardless of the 
grade, may also be considered as DLT. 
DLTs will be handled as well as Adverse Event of Special Interest (AESI) (See Section 10.5.5). 
As such, the investigators will be required to report them to Sanofi within 24 hours of investigator 
awareness of each event. 
Before starting Cohort 2 and Phase II part, all safety data, and the reported potential DLTs will be 
reviewed to determine their relationship to the IMP. Starting Cohort 2 or Phase II part decisions 
will be based on the assessment of IMP related DLTs by the Study Committee.  
Dose escalation will be stopped if ≥33% (≥2 in up to 6 patients) of patients experienced an IMP 
related DLT observed during the first cycles of treatment (4 weeks), according to the definition of 
MAD. 
Although the DLT evaluation process is guided by the safety evaluation during the first cycle of 
treatment, cumulative toxicities observed in subsequent administrations should also be considered 
for the dose escalation and the dose selection decisions, upon agreement within the Study 
Committee. 
9.1.2 Adverse Events  
Safety profile will be based on incidence, severity (as graded by the NCI CTC AE v. 4.03), and 
cumulative nature of treatment-emergent AEs (TEAEs). TEAEs are defined as AEs that develop, 
worsen or became serious during the on-treatment period. For this study, the on-treatment period 
will be defined as the period from the time of first dose of IMP to at least 30 days after last 
administration of the IMP. Each patient will be assessed preferably by the same physician for AEs 
and according to the NCI CTC AE v. 4.03 classification. 
Adverse events will be coded to “Preferred Term (PT)” and associated primary “System Organ 
Class (SOC)” using MedDRA (Medical Dictionary for Regulatory Activities). AEs will be 
summarized with respect to the type, frequency, severity, seriousness, and relatedness. 
9.1.3 Laboratory Safety Variables  
Please refer to “Study Procedures” Section 12. 
9.1.4 Clinical Examinations  
Please refer to “Study Procedures” Section 12. 
9.1.5 Vital Signs  
Please refer to “Study Procedures” Section 12 for assessment timings. Vital signs consist of 
examination of blood pressure, heart rate, temperature, and respiration rate. 
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9.1.6 ECG  
Please refer to “Study Procedures” Section 12 for assessment timings of the 12-lead ECG and 2-D 
Echocardiogram/ MUGA. 
9.1.7 Chest X-Ray  
Please refer to “Study Procedures” Section 12 for assessment timings. Chest X-Ray to be 
performed for assessment of pulmonary disease condition. 
9.1.8 Immunogenicity  
Human anti-drug antibodies to isatuximab will be assessed throughout the study. Blood samples 
will be collected for ADA detection according to the PK flowchart (see Section 1.7 or  
Section 1.8). 
In case of positivity or inconclusive sample at 60 days post last IMP administration, additional 
assessment of ADA will be performed every month until sample is negative. If ADA is positive at 
Cycle 10, one additional sampling for ADA evaluation should be collected 3 months later. No 
further ADA will be collected, even if the 3-month sample is positive. 
Detailed instructions for ADA sample preparation and shipping will be provided to the study sites 
in a separate Laboratory Manual. 
9.1.9 Other Clinical Assessments  
• 
Safety laboratory assessments: Please refer to “Study Procedures” Section 12. 
• 
Results of additional procedures (such as karyotype, fluorescence in situ hybridization 
[FISH], etc.) performed as part of standard of care to assess the current disease status may 
also be collected. 
9.2 
PHARMACOKINETIC EVALUATION  
9.2.1 Sampling Time and Sample Blood Volume  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples missed or lost, for any reason should be recorded. Actual times of blood collection 
should be recorded in the e-CRF.  The days of sampling and times of drug administration should 
also be precisely recorded. 
The sampling times for blood collection can be found in the PK Flow Chart (Section 1.7 or 
Section 1.8). 
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9.2.2 Pharmacokinetic Sample Handling Procedure 
Detailed instructions for PK sample preparation and shipping are summarized in Table 5.  Further 
details will be provided to the study sites in a separate Laboratory Manual. 
Table 5 - Summary of handling procedures 
PK 
ADA 
Sample volume: 
3 mL of blood 
3 mL of blood 
Anticoagulant Tube Type: 
Blood will be collected into EDTA tube 
Blood will be collected into EDTA tube 
Handling procedure 
Blood with centrifuged at 2000g for 20 min 
at 4°C within 30 min of sampling time 
Blood with centrifuged at 2000g for 20 min 
at 4°C within 30 min of sampling time 
Plasma aliquot split 
2 samples, 0.5 mL in aliquot 1 and the 
remaining in aliquot 2 
2 samples, 0.5 mL in aliquot 1 and the 
remaining in aliquot 2 
Plasma storage conditions 
Polypropylene tubes with screw caps and 
frozen promptly (within 1 hour after 
collection of blood) at (-)80°C. 
Polypropylene tubes with screw caps and 
frozen promptly (within 1 hour after 
collection of blood) at (-)20°C. 
Plasma shipment conditions 
Dry ice 
Dry ice 
9.2.3 Bioanalytical Method  
A brief outline of the bioanalytical assay is given in Table 6. Also, see laboratory manual. 
Table 6 - Bioanalytical method for isatuximab in plasma 
Analyte 
isatuximab 
ADA 
Matrix : 
Plasma 
Plasma 
Analytical technique : 
ELISA 
Pand A 
Lower limit of quantification: 
 0.5 ng/mL 
n.a.
Assay volume: 
 100 µL 
 100 µL 
Site of bioanalysis: 
Sanofi R&D DSAR, 
 
 
Sanofi R&D DSAR, 
 
 
9.2.4 Pharmacokinetic Parameters 
Pharmacokinetic analyses will be carried out in the Sponsor Disposition, Safety, and Animal 
Research department.  Pharmacokinetic parameters will be calculated with PKDMS software 
(Pharsight), using non-compartmental methods from plasma isatuximab concentrations obtained 
after 1st administration. 
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The parameters will include, but may not be limited to the following: 
Table 7 - List of pharmacokinetic parameters and definitions  
Parameters 
Drug  
Matrix 
Definition/calculation 
Ceoi 
isatuximab 
Plasma 
Concentration observed at the end of infusion 
Cmax 
isatuximab 
Plasma 
Maximum concentration observed 
Ctrough 
isatuximab 
Plasma 
Plasma concentration observed just before treatment 
administration during repeated dosing 
tmax 
isatuximab 
Plasma 
First time to reach Cmax 
AUC1 week  
isatuximab 
Plasma 
Area under the plasma concentration versus curve 
calculated using the trapezoidal method over the dosing 
interval 
 
Blood concentrations of isatuximab will be also used for population PK analysis by non-linear 
mixed effects modeling. Additional details of the analysis plan and the results could be provided 
in a separate document. 
9.3 
EFFICACY  
9.3.1 Criteria for Response  
ORR is defined as the proportion of patients with stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), and partial response (PR) based on responses 
as assessed using the International Myeloma Working Group (IMWG) Uniform Response Criteria 
(see Appendix C). Response evaluation will be performed on a monthly basis. The best overall 
response for each patient will be determined by independent adjudication committee. 
All responses (sCR, CR, VGPR, PR) should be confirmed on 2 consecutive laboratory efficacy 
parameters assessments according to study flow-chart (approximately 4 weeks interval). Stable 
disease (SD) does not require confirmation. Disease progression by paraprotein should be 
confirmed on within the first 4 weeks after last assessment. Disease progression based on 
imaging, bone marrow plasma cell percentage, or hypercalcemia (not attributable to any other 
cause) do not need to be confirmed. 
Clinical benefit rate (CBR): defined as the proportion of patients with sCR, CR, VGPR, PR or 
MR according to IMWG criteria. 
Duration of response (DOR): defined as the time from the date of the first response to the date of 
subsequent progressive disease (PD) or death, whichever happens earlier. 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 assessment performed before the analysis cut-off date 
or date of initiation of new anticancer treatment, whichever is earlier. DOR is determined only for 
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patients who have achieved a response of ≥PR. DOR will not be calculated for patients that do not 
achieve a response. 
Overall survival (OS): defined as the time interval from the date of first study treatment 
administration to death due to any cause. In the absence of the confirmation of death before the 
analysis cutoff date, OS will be censored at the last date the patient is known to be alive or at the 
study cutoff date, whichever is earlier. 
Progression free survival (PFS): defined as the time interval from the date of first study treatment 
administration to the date of the first assessed disease progression or death due to any cause, 
whichever comes first. In the absence of disease progression or death before the analysis cutoff 
date, or the date of initiation of new anticancer treatment, PFS will be censored at the date of the 
last valid assessment performed before the cutoff date or the date of initiation of new anticancer 
treatment, whichever is earlier. 
Time to progression (TTP): defined as the time interval from the date of first study treatment 
administration to the date of the first assessed disease progression. In the absence of disease 
progression before the analysis cutoff date, or the date of initiation of new anticancer treatment, 
TTP will be censored at the date of the last valid assessment performed before the cutoff date or 
the date of initiation of new anticancer treatment, whichever is earlier. 
Response evaluation will include: 
• 
M-protein quantification (serum and 24 hours urine) 
• 
Serum free light chain (FLC) levels 
• 
Bone marrow aspiration and/or biopsy 
• 
CT/MRI scan of plasmacytoma (medullary and extramedullary) 
• 
Bone skeletal survey 
• 
Corrected serum calcium 
9.4 
SPECIFIC ASSESSMENTS  
9.4.1 CD38 Receptor Density Assessment  
Brief instructions for the sample handling and the analytical method are summarized in Table 8.  
Further details will be provided to the study sites in a separate Laboratory Manual. 
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Table 8 - Sample handling procedure and Analytical method for CD38 receptor density assessment  
Sample handling procedure 
 
Analytical method 
Sample volume: 
2 mL of bone marrow 
 
Matrix: 
bone marrow 
Anticoagulant Tube Type: 
Bone marrow will be collected 
into EDTA tube 
 
Analytical technique: 
Flow cytometry 
Handling procedure 
Refer to operator manual 
 
Lower limit of quantification: 
n.a. 
Plasma aliquot split 
Refer to laboratory manual 
 
Assay volume: 
2 mL 
Plasma storage conditions 
Refer to laboratory manual 
 
Site of bioanalysis: 
Sanofi R&D DSAR 
Plasma shipment conditions 
Ambient temperature 
 
 
 
9.4.2 Minimal Residual Disease Assessment  
• 
Minimal residual disease (MRD) will be assessed by next generation sequencing of 
leukocyte DNA in bone marrow samples from CR patients and correlated with parameters 
of clinical response.  
Traditional method to measure MRD include multiparametric flow cytometry (MFC) and 
more recently next generation sequencing to amplify and sequence immunoglobulin gene 
segments present in myeloma clone is a quantitative method for MRD detection. Bone 
marrow aspirate/biopsy samples will be collected at baseline/screening and the time of 
CR.  
9.4.3 Exploratory Biomarker Studies  
Please refer to “Study Procedures” Section 12 for assessment timings. 
Bone marrow and blood samples will be collected for the following purpose: 
• 
Bone marrow aspirates/biopsy sample will be collected at screening/ baseline. 
Cytogenetics analyses will be performed and correlated with parameters of clinical 
response. Suggested FISH probes include, but may not limited to, those for del(17p), t (4, 
14) and t(14; 16). 
• 
Correlation of immune genetic determinants (FcγR polymorphisms, HLA and KIR 
genotypes) with parameters of clinical response. DNA will be extracted from peripheral 
blood leukocytes. Sequence-specific PCR and Sanger sequencing of selected exomes will 
be performed. These analyses will not reveal the entire nucleotide sequence of the target 
gene. 
• 
Correlation of immunophenotype in bone marrow and/or peripheral blood with parameters 
of clinical response. Immune cell populations (including B-cell, T-cell and NK cell 
subsets) will be characterized by multiparametric flow cytometry analysis on the 
expression of cell surface markers. The proportion of cells positive for a given marker or 
set of markers will be correlated with response to isatuximab.  
• 
Soluble CD38 levels in peripheral blood will be correlated with parameters of PK and 
clinical response. Other soluble factors in blood may also be analyzed. 
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Special procedures for processing and shipping of biomarkers samples are described in detail in 
the laboratory manual. 
No sample banking is planned. The samples that are remaining after the testing may be used for 
potential exploratory research related to the drug action and/or effect of isatuximab pending 
evolving literature. DNA samples will not be used for broad exploratory unspecified disease or 
population genetic analysis.  
All remaining samples will be discarded within 5 years after the end of the study. The remaining 
samples will be discarded if the patients withdrew from the study consent.  
These samples will remain labelled with the same identifiers than the one used during the study 
(ie, subject 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 subject confidentiality and personal data.  
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10 
PATIENT SAFETY  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
The NCI CTCAE v.4.03 will be used in this study to grade clinical and laboratory AEs.  
Please also refer to Section 9.1. 
10.2 
SAFETY INSTRUCTIONS  
The safety of the patients in this clinical trial is primarily dependent on the clinical Investigators’ 
monitoring and assessment of their patients.  For IARs, please refer to Section 6.6.1. 
10.3 
ADVERSE EVENTS MONITORING  
All AEs will be managed and reported in compliance with all applicable regulations, and included 
in the final clinical study report. 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT  
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered with a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
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 event: 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. 
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Note: Examples of such events (list is not exhaustive) are intensive treatment in an emergency 
room or at home (for allergic bronchospasm, blood dyscrasia, or convulsions) or asymptomatic 
ALT increase ≥10 ULN that does not result in hospitalization, or development of drug 
dependency or drug abuse. 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.5.1 Adverse Events  
All AEs regardless of seriousness or relationship to the IMP, spanning from the signature of the 
informed consent form (ie, occurring during the baseline period even in the absence of any 
administration of IMP), up to 30 days following the last administration of study treatment, are to 
be recorded on the corresponding page(s) included in the e-CRF. 
Whenever possible, diagnosis or single syndrome should be reported instead if symptoms.  The 
Investigator should specify the date of onset, intensity, action taken with respect to IMP, 
corrective treatment/therapy given, additional investigations performed, outcome, and his/her 
opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
requiring corrective treatment and/or leading to treatment discontinuation and/or modification of 
dosing and/or fulfilling a seriousness criterion and/or is defined as an AESI (see Section 10.5.5). 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a seriousness criterion and/or are defined as an AESI 
(see Section 10.5.5). 
10.5.2 Serious Adverse Events, Adverse Events of Special Interest, Pregnancy and 
Symptomatic Overdose  
In the case of a SAE, an AESI, a pregnancy report, or a symptomatic overdose, the Investigator 
must immediately: 
• 
ENTER (within 24 hours) the information related to a SAE, an AESI, a pregnancy report 
or a symptomatic overdose in the appropriate screens of the e-CRF; the system will 
automatically send e-notification to the monitoring team after approval of the Investigator 
within the e-CRF or after a standard delay. 
• 
There may be instances when copies of medical records for certain cases are requested by 
Sanofi. In such case, care should be taken to ensure that the patient's identity is protected 
and the patient's identifiers in the study are properly mentioned on any copy of a source 
document provided to the Company. For laboratory results, include the laboratory normal 
ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate 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. 
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• 
A back-up plan is used (using paper flow) when the e-CRF system does not work. 
• 
During the Phase I part, the monitoring team will notify the study investigators of the 
occurrence of DLTs within 24 hours. 
10.5.3 Follow-up  
• 
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 
or other, etc.) until the return to normal or consolidation of the patient's condition.  
Ongoing related AEs at the end of study treatment will be followed until resolution or 
stabilization. 
• 
In case of any SAE/AESI, the 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 discontinued 
study treatment or has left the clinical trial and that additional investigations may be 
requested by the monitoring team; 
• 
In case of any SAE or AESI brought to the attention of the Investigator at any time after 
the end of the study for the patient and considered by him/her to be caused by the IMP 
with a reasonable possibility, should be reported to the monitoring team. 
10.5.4 Treatment discontinuation due to non-serious adverse event  
In the case of a treatment discontinuation due to a non-serious AE: 
• 
ENTER (within 24 hours) the information related to treatment discontinuation due to a 
non-SAE in the appropriate screens of the e-CRF (AE with the box "action taken with 
IMP" ticked "drug withdrawn", together with the end of treatment form with reason that 
should be ticked "AE"); the system will automatically send the notification to the 
monitoring team after approval of the Investigator within the e-CRF or after a standard 
delay. 
10.5.5 Adverse Event of Special Interest  
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to 
isatuximab, for which ongoing monitoring and immediate notification by the Investigator to the 
Sponsor is required.  Such events may require further investigation in order to characterize and 
understand them.  Adverse events of special interest may be added or removed during a study by 
protocol amendment. 
The following adverse events are considered AESIs: 
• 
Acute infusion associated reactions (IARs; see Appendix G for diagnoses and symptoms 
typical of an IAR). An IAR is a related adverse event with onset within 24 hours from the 
start of the infusion. As defined in Section 10.5.1, a main diagnosis and individual 
symptoms should be reported in the e-CRF. However, only the main diagnosis will be 
reported as AESI. 
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• 
During Phase I part, all protocol–defined potential or IMP related DLTs (as defined in 
Section 9.1.1) are considered AESIs, and as such, the Investigators will be required to 
report them to the Sponsor within 24 hours of the Investigator becoming aware of the 
adverse event. The Investigator will attach the DLT-specific CRF page to the DLT/AESI 
form. 
Pregnancy occurring in a female patient entered in the clinical trial or in a female partner of a 
male patient entered in the clinical trial. It will be qualified as an SAE only if it fulfills one of the 
seriousness criteria (see Section 10.4).   
• 
Symptomatic overdose (serious or non-serious) with IMP 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator. 
10.5.6 Pregnancy  
• 
Pregnancy will be recorded as an AE in all cases.  It will be qualified as a SAE only if it 
fulfils SAE criteria. 
• 
In the event of pregnancy, IMP should be discontinued and the Sponsor should be 
informed immediately (within 24 hours), even if the event does not fulfil the criteria for a 
SAE, 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 this protocol. 
• 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
10.5.7 Symptomatic Overdose  
In case of accidental or intentional overdose of IMP (at least 30% above the intended 
administered dose at each cycle expressed in unit per body weight) with any symptoms, 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 e-CRF. 
Asymptomatic overdose has to be reported as a standard AE. 
10.5.8 Laboratory Abnormalities  
Laboratory abnormalities should be monitored, documented, and managed according to the 
related flowchart (see Section 1.4 and Section 1.5). Laboratory values will be reported in the 
appropriate pages of e-CRF. 
Laboratory abnormalities should be reported as AE only in case they lead to an action on study 
treatment or if there are serious (see Section 10.5.1). 
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10.6 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are unexpected and are at least reasonably related to the IMP (ie, suspected 
unexpected serious adverse reactions [SUSARs]), to the regulatory authorities, 
Institutional Review Boards (IRBs) as appropriate and to the Investigators. 
• 
All SAEs those are expected and at least reasonably related to the IMPs, AESI (see list in 
Section 10.5.5) to the regulatory authorities, according to local regulations. 
• 
During Phase I part, when cohorts of more than one patient begin accruing, the monitoring 
team will notify the study investigators of the occurrence of DLTs and AESI within 
24 hours. 
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT 
TREATMENT DISCONTINUATION AND OF PATIENT STUDY 
DISCONTINUATION  
Patients are free to withdraw their participation at any time during this clinical trial. The 
investigator has the right to remove any subject from treatment with study drug or participation in 
the study. However, the Sponsor requests that the investigator consult with the Sponsor Clinical 
Study Director before prematurely removing a subject. 
Patients, who decide to withdraw from the study, or meet the withdrawal criteria, should undergo 
an End of Treatment visit. See Section 12.4. 
Pregnancy in female subjects will lead to definitive treatment discontinuation in all cases. 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL 
MEDICINAL PRODUCT(S)  
11.1.1 List of Criteria for Permanent Treatment Discontinuation  
Patients may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be done at the discretion of the Investigator.  All efforts 
should be made to document the reason for discontinuation and this should be documented in the 
e-CRF. 
Treatment with the IMP should be discontinued in any of the following cases: 
• 
At the patient’s request, at any time and irrespective of the reason (consent’s withdrawal).   
• 
If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing, such as: 
- 
Disease progression. 
- 
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). 
• 
Patient is lost to follow-up. 
• 
Sponsor decision to discontinue the study. 
If patients are clinically stable, 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 6.6.3. 
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11.1.2 Handling of Patients after Permanent Treatment Discontinuation  
All permanent treatment discontinuation should be recorded by the Investigator in the appropriate 
screen of e-CRF when considered as confirmed.  After study treatment is discontinued, patients 
should complete a follow-up visit 30 days after the last administration of the IMP as described in 
Section 12.4. 
Patients who have been withdrawn from the study treatment cannot be re-entered into the study. 
11.1.3 Temporary Treatment Discontinuation with Investigational Medicinal Product(s)  
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs.  Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator has deemed it appropriate according to his/her best 
medical judgment and considers that the causality of the AE was unlikely related to the IMP(s).  
The patient must continue to meet the safety related selection criteria (refer to Section 7.2 and 
Section 7.3). 
For all temporary treatment discontinuations, the duration of the discontinuation should be 
recorded by the Investigator in the appropriate pages of the e-CRF.  
11.2 
REPLACEMENT OF PATIENTS  
During the Phase I part of the study, a patient may be considered not evaluable for DLT and may 
be replaced at the same dose level as described in Section 6.3. 
Patients treated in the Phase II part of the study who are withdrawn from study treatment will not 
be replaced. 
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12 
STUDY PROCEDURES  
12.1 
VISIT SCHEDULE  
During the course of the study, all patients entering the study must be evaluated according to the 
schedule outlined in the flow charts in Section 1 and described below. The results of the 
evaluation will be recorded in the e-CRF pages until the patient is not followed anymore. After 
the screening/ baseline visit, all eligible patients included in the study will have a visit on site as 
detailed below. A complete visit will be performed at EoT (30 days +/- 7 days after the last 
administration of the IMP). The patients will be followed until recovery or consolidation of any 
SAE or IMP-related AE. Additionally, ADA samples are required (60 days +/- 7 days after last 
IMP administration). 
12.2 
BASELINE EVALUATION  
The pretreatment examinations are to be performed within 21 days (unless specified otherwise) 
prior to the first administration of the IMP.  The informed consent form will have to be signed by 
the patient before any procedure specific to the study can be performed.  The following 
assessments are to be performed at this visit.  
If the patient cannot be registered within 21 days of informed consent, the same patient may be re-
screened after discussion with the sponsor, provided that there are no persisting safety concerns 
for patient’s study participation. The informed consent form will have to be re-signed by the re-
screened patient before starting re-screening procedures. New patient number will be given for the 
re-screened patients. 
• 
Inform to the registration center 
• 
Medical History and Clinical Examinations:  
- 
Demography: Includes date of birth, gender and race. 
- 
Medical/Surgical History: includes relevant history of previous/associated pathologies 
other than multiple myeloma. 
- 
Disease History: includes date of initial diagnosis of MM, subtype, stage of 
international stating system (see Appendix F), previous anti-MM therapy (drug name 
by line of therapy, start and end date of administration, reason for discontinuation, best 
response and date of progression/relapse), disease status at inclusion (refractory to last 
IMiD or  PI included therapy). In addition, results of additional procedures (such as 
karyotype, fluorescence in situ hybridization (FISH), etc.) performed as part of 
standard of care to assess the current disease status may also be collected. 
- 
Physical Examination: consists of examination of major body systems including 
neurological, digestive, extramedullary myeloma localizations, respiratory, 
hepatomegaly, splenomegaly, lymphadenopathy. 
- 
Weight and Height 
- 
Vital signs: includes heart rate, temperature, respiratory rate, blood pressure.  
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- 
Performance Status (ECOG) 
- 
Prior medications given within 7 days prior to first dose. 
- 
Adverse events/serious adverse events are to be reported from the signing of the 
informed consent. 
• 
12-lead ECG 
• 
2-D Echocardiogram or Multigated Acquisition (MUGA) scan 
• 
Chest X-ray 
• 
Laboratory Assessments: 
- 
Hematology: includes hemoglobin, hematocrit, RBC, WBC with differential, Mean 
Corpuscular Volume (MCV) and platelet count.  
- 
Serum Chemistry: includes SGOT (AST), SGPT (ALT), bilirubin (total and direct), 
alkaline phosphatase, lactate dehydrogenase (LDH), fasting glucose, sodium, 
potassium, chloride, magnesium, calcium/ corrected serum calcium, phosphate, uric 
acid, blood urea nitrogen (BUN), serum creatinine and eGFR (Revised equations for 
eGFR in Japanese), albumin and total protein.  
- 
Coagulation: includes PT or INR, and aPTT. 
- 
Urinalysis: includes blood, protein, glucose, pH, ketones, bilirubin, leucocytes, nitrites 
and specific gravity. 
- 
Pregnancy Test: women of child bearing potential must have a negative serum 
pregnancy test result within 7 days prior to first IMP administration. 
- 
HBs-Ag, HBc-Ab, HBs-Ab, HCV-Ab tests. If HBc-Ab and/or HBs-Ab positive at 
baseline, HBV-DNA test is required prior to registration. If history of HBV infection is 
suspected, monitoring of HBV-DNA is recommended on Day 1 of each cycle. 
- 
HIV-Ab tests (Testing is not required unless there is a suspicion of virus infection.) 
• 
Disease Assessment: 
- 
Myeloma-specific Lab Tests: 
- 
M-protein quantification (serum electrophoresis and immunofixation and 24-hour 
urine collection for Bence Jones protein with urine electrophoresis and 
immunofixation) 
- 
Serum free light chain levels 
- 
Serum β2-microglobulin 
- 
Immunoglobulins: IgG, IgA, IgM, IgD and IgE 
- 
Corrected serum calcium 
- 
Bone marrow aspiration to be performed.  
In case of dry-tap, bone marrow biopsy to be performed. 
(For subsequent cycle, only required to confirm a CR) 
- 
Extramedullary Disease: Radiologic imaging (CT/MRI scan) of plasmacytoma. 
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- 
Skeletal survey: X-ray. 
X-ray skeletal survey should include radiographs of the following: lateral skull; 
Postero-Anterior (PA) chest; Antero-Posterior(AP) and lateral cervical spine; AP and 
lateral thoracic spine; AP and lateral lumbar spine; AP pelvis; AP upper extremities, 
shoulder to elbow, bilateral; and AP lower extremities, hip to knee, bilateral. 
• 
Biomarker/ Exploratory Studies: 
- 
CD38 Receptor Density in bone marrow. 
- 
Cytogenetics/FISH in screening/ baseline bone marrow sample. Probes for 
fluorescence in situ hybridization (FISH) analysis may include t(4;14), t(14;16) and 
del(17p). 
- 
Immune phenotyping (bone marrow). 
- 
MRD assessment in bone marrow: baseline sample will be used as reference to 
determine major disease clone(s). 
(For subsequent cycle, only required to confirm a CR) 
All patients who signed the study informed consent form will be assigned a patient number.  
Each patient will receive an incremental identification number corresponding to his/her order 
of enrollment in the study.  Those patients, who meet all the inclusion criteria and none of the 
exclusion criteria, will be eligible for registration in the study.  A written confirmation of each 
eligible patient identification and treatment dose level will be forwarded to the Investigator.  
12.3 
DURING THE TREATMENT PERIOD  
See flow charts in Section 1.4 and Section 1.5 
12.3.1 Day 1 of Each Cycle  
All patients who are going to continue study treatment after completing Cycle 1 must sign a 
second ICF before commencing IMP administration. (Phase I part Cycle 2 only) 
The evaluations below are to be performed prior to first IMP administration on Day 1 of each 
cycle unless otherwise indicated. 
• 
Inform to the registration center (Cycle 1 only) 
• 
Patient Registration (Cycle 1 only) 
• 
Clinical Examinations: 
- 
Physical Examination 
- 
Performance Status (ECOG) 
- 
Weight 
- 
Vital signs  
(to be taken pre-infusion, mid-infusion (when half the volume is administered), and 
end-infusion on days of IMP administration. If the infusion rate changes because of an 
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infusion-associated reaction, vital signs should be monitored every hour and at the end 
of the infusion.) 
- 
AE/ SAE assessment 
- 
Concomitant Medications 
• 
Laboratory Assessments: 
- 
Hematology 
(not required to be repeated at Cycle 1 Day 1 if screening labs were performed within 
3 days prior to first IMP administration) 
Perform direct and indirect coombs tests prior to the first IMP administration. 
- 
Serum Chemistry 
(not required to be repeated at Cycle 1 Day 1 if screening labs were performed within 
3 days prior to first IMP administration) 
- 
If history of HBV infection is suspected, perform HBV-DNA test on Day 1 of each 
cycle. 
- 
Urinalysis: Quantitative urinalysis will be needed if hematuria is observed or clinically 
indicated. 
(not required to be repeated at Cycle 1 Day 1 if screening labs were performed within 
3 days prior to first IMP administration) 
- 
Pregnancy Test: Not required at Cycle 1 Day 1 if a negative serum pregnancy test 
result available within 7 days prior to first IMP administration. Urine test can be used 
at Day 1 of each subsequent cycle. 
- 
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL 
increase in HBV DNA or reappearance of HBsAg or detection of HBV DNA in 
patients with resolved infection), ALT and AST will be closely monitored every month 
up to study treatment discontinuation. HBV DNA to be done as per specialist advice 
(Phase II part, Subsequent Cycles only). 
• 
Disease Assessment: 
- 
Myeloma-specific Lab Tests:  
(not required to be repeated at Cycle 1 if screening labs were performed within 3 days 
prior to first IMP administration) 
-   M-protein quantification (serum and 24-hours urine) 
-   Serum β2-microglobulin to be performed if clinically indicated 
-   Immunoglobulins: IgG, IgA and IgM (IgD or IgE test to be performed if positive at 
baseline) 
-   Corrected serum calcium 
-   Serum and urine immunofixation and free light chain tests to be performed to 
confirm a CR and as clinically indicated. 
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- 
Extramedullary Disease (approximately every 12 weeks, eg. Cycle 4, 7, 10): Required 
if positive at screening/ baseline as determined by Independent Adjudication 
Committee.  
- 
Skeletal survey (Cycle ≥2):  only required if clinically indicated or to confirm response 
according to IMWG criteria. CT/MRI scans can also be performed if clinically 
indicated or to confirm response according to IMWG criteria. 
• 
PK (up to 10 cycles) and ADA (refer to Section 1.7 and Section 1.8) 
• 
Biomarker/ Exploratory Studies: 
- 
Immune genetic determinants in peripheral blood: including Killer cell Ig-like 
receptors (KIR), HLA Typing and FcγR genes (Cycle 1 only). 
- 
Peripheral blood for soluble CD38 (Cycle 1 only). 
- 
Peripheral blood for Immune phenotyping (Cycle 1 and 3 only). 
Administration of isatuximab 
Isatuximab Safety Labs:  
Should a isatuximab infusion associated reaction of Grade ≥2 occur, additional blood 
sampling during the AE is required for analysis of markers of potential tumor lysis syndrome 
(uric acid, lactate dehydrogenase [LDH], BUN, creatinine, potassium, phosphate, ionized or 
corrected calcium). 
Bone marrow aspirates/biopsy will be collected in CR suspected patients for MRD analysis. 
12.3.2 Day 2, 3, 4 of Cycle 1 of Phase I part  
• 
PK (refer to Section 1.7) 
12.3.3 Day 8 and Day 22 of Cycle 1  
The evaluations below are to be performed prior to IMP administration on Day 8 and 22 of Cycles 
1 only. 
• 
Clinical Examinations: 
- 
Physical Examination 
- 
Weight 
- 
Vital signs 
(to be taken pre-infusion, mid-infusion (when half the volume is administered), and 
end-infusion on days of IMP administration. If the infusion rate changes because of an 
infusion-associated reaction, vital signs should be monitored every hour and at the end 
of the infusion.) 
- 
AE/ SAE assessment 
- 
Concomitant Medications 
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• 
Laboratory Assessments: 
- 
Hematology 
- 
Serum Chemistry 
• 
PK and ADA (refer to Section 1.7 and Section 1.8) 
Administration of isatuximab 
Isatuximab Safety Labs (if ≥Grade 2 infusion associated reaction) 
12.3.4 Day 15 of Each Cycle  
The evaluations below are to be performed prior to IMP administration on Day 15 of each cycle 
unless otherwise indicated. 
• 
Clinical Examinations: 
- 
Physical Examination (Cycle 1, 2, 3 only) 
- 
Weight 
- 
Vital signs  
(to be taken pre-infusion, mid-infusion (when half the volume is administered), and 
end-infusion on days of IMP administration. If the infusion rate changes because of an 
infusion-associated reaction, vital signs should be monitored every hour and at the end 
of the infusion.) 
- 
AE/ SAE assessment 
- 
Concomitant Medications 
• 
Laboratory Assessments: 
- 
Hematology 
- 
Serum Chemistry 
- 
Urinalysis: Quantitative urinalysis will be needed if hematuria is observed or clinically 
indicated. 
- 
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL 
increase in HBV DNA or reappearance of HBsAg or detection of HBV DNA in 
patients with resolved infection), ALT and AST will be closely monitored every month 
up to study treatment discontinuation. HBV DNA to be done as per specialist advice 
(Phase II part, Subsequent Cycles only). 
• 
PK (refer to Section 1.7 and Section 1.8, up to 10 cycles) 
• 
ADA (Cycle 1 only) 
Administration of isatuximab 
Isatuximab Safety Labs 
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12.4 
END OF TREATMENT VISIT (TO BE PERFORMED 30 DAYS (+/- 7 DAYS) AFTER THE 
LAST ADMINISTRATION OF THE INVESTIGATION MEDICINAL PRODUCT)  
• 
Inform to the registration center 
• 
Clinical Examinations: 
- 
Physical Examination 
- 
Performance Status (ECOG) 
- 
Weight 
- 
Vital signs 
- 
AE/ SAE assessment 
- 
Concomitant Medications 
• 
Laboratory Assessments: 
- 
Hematology 
- 
Serum Chemistry 
- 
If history of HBV infection is suspected, perform HBV-DNA test. 
- 
Urinalysis: Quantitative urinalysis will be needed if hematuria is observed or clinically 
indicated. 
- 
Serum Pregnancy Test 
• 
Disease Assessment: 
- 
Myeloma-specific Lab Tests:  
-   M-protein quantification (serum electrophoresis and immunofixation and 24-hour 
urine collection for Bence Jones protein with urine electrophoresis and 
immunofixation) 
-   Serum free light chain levels 
-   Serum β2-microglobulin 
-   Immunoglobulins: IgG, IgA, IgM, IgD and IgE 
-   Corrected serum calcium 
- 
Extramedullary Disease (approximately every 12 weeks, eg. Cycle 4, 7, 10): Required 
if positive at screening/ baseline as determined by Independent Adjudication 
Committee. May be omitted at End of Treatment if conducted within 12 weeks.  
• 
PK and ADA (refer to Section 1.7 and Section 1.8) 
• 
Biomarker/ Exploratory Studies: 
- 
Immune phenotyping (peripheral blood sample) 
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12.5 
FOLLOW-UP VISIT (TO BE PERFORMED 60 DAYS (+/- 7 DAYS) AFTER THE LAST 
ADMINISTRATION OF THE INVESTIGATION MEDICINAL PRODUCT)  
• 
Inform to the registration center. 
• 
Clinical Examinations: 
- 
AE/SAE Assessment (all ongoing related AE, ongoing SAE/AESIs, and new related 
AE/SAE/AESIs are to be followed up to resolution or stabilization) 
- 
Concomitant Medication (if for related AE, ongoing SAE/AESIs, and new related 
AE/SAE/AESIs) 
- 
The first new anticancer therapy after the last IMP administration. 
• 
Disease Assessment:  
Disease assessments during follow-up period are only required for patients with PR or 
better who have discontinued study treatment for reasons other than disease progression 
and have not yet started treatment with another anti-cancer therapy. Disease assessments 
will be done up to PD, initiation of further anti-cancer therapy or second cut-off date, 
whichever comes first. Patients will be followed every 4 weeks for progression during this 
period. Disease assessments required every 4 weeks is myeloma-specific lab tests. 
Extramedullary disease assessment is required approximately every 12 weeks or upon 
clinical suspicion of progressive disease. All imaging will be sent to a central imaging lab. 
A bone marrow aspiration and/or biopsy, skeletal survey are only required if clinically 
indicated to confirm response or progression according to IMWG criteria.  
- 
Myeloma-specific Lab Tests:  
-   M-protein quantification (serum and 24-hours urine) 
-   Serum β2-microglobulin to be performed if clinically indicated 
-   Immunoglobulins: IgG, IgA, IgM (IgD or IgE test to be performed if positive at 
baseline) 
-   Corrected serum calcium 
-   Serum and urine immunofixation and free light chain tests to be performed to 
confirm a CR and as clinically indicated. 
- 
Extramedullary Disease: Required if positive at screening/ baseline as determined by 
Independent Adjudication Committee. 
• 
ADA (refer to Section 1.7 and Section 1.8): if patient is positive for ADA or the sample is 
inconclusive, additional ADA samples are required every month (± 7 days) until sample is 
negative. 
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12.6 
PERIOD POST 60 DAYS FOLLOW-UP PERIOD  
• 
Clinical Examinations: 
- 
New anticancer therapy 
- 
AE/SAE Assessment (all ongoing related AE, ongoing SAE, and new related 
AE/SAEs are to be followed up to resolution or stabilization) 
- 
Concomitant Medication (if for related AE, ongoing SAE, and new related AE/SAEs) 
• 
Survival Status:  
Patients will also be followed for survival status approximately every 3 months from the 
date of last IMP administration until death or second cut-off date, whichever comes first. 
Every effort will be made to follow all patients. If survival follow-up is missed and is not 
obtained at the time of the scheduled interval, it should be obtained immediately. For 
subsequent survival follow-up, the patient should be contacted at the original scheduled 
survival follow-up interval. If the patient is unable to visit the clinical center, the follow-up 
may be done via phone from the Investigator or designee to the patient or the patient's 
caregiver or a family member. 
• 
Disease Assessment:  
Disease assessments during follow-up period are only required for patients with PR or 
better who have discontinued study treatment for reasons other than disease progression 
and have not yet started treatment with another anti-cancer therapy. Patients will be 
followed every 4 weeks for progression during this period. Disease assessments required 
every 4 weeks is myeloma-specific lab tests. Extramedullary disease assessment is 
required approximately every 12 weeks or upon clinical suspicion of progressive disease. 
All imaging will be sent to a central imaging lab. A bone marrow aspiration and/or biopsy, 
skeletal survey are only required if clinically indicated to confirm response or progression 
according to IMWG criteria. Disease assessments not required once patient starts 
treatment with another anti-cancer therapy. 
- 
Myeloma-specific Lab Tests:  
(For patients with PR or better who have discontinued study treatment for reasons 
other than disease progression and have not yet started treatment with another anti-
cancer therapy only) 
-   M-protein quantification (serum and 24-hours urine) 
-   Serum β2-microglobulin to be performed if clinically indicated 
-   Immunoglobulins: IgG, IgA and IgM (IgD or IgE test to be performed if positive at 
baseline) 
-   Corrected serum calcium 
-   Serum and urine immunofixation and free light chain to be performed to confirm a 
CR and as clinically indicated. 
- 
Extramedullary Disease: Required if positive at screening/ baseline as determined by 
Independent Adjudication Committee. 
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• 
ADA:  
If patient is positive for ADA or the sample is inconclusive, additional ADA samples are 
required every month (± 7 days) until sample is negative. 
12.7 
POST SECOND ANALYSIS CUT-OFF PERIOD  
If a patient continues to benefit from the treatment after the second analysis cut-off date, the 
patient can continue study treatment. Such patients will be followed until 60 days after the last 
administration of the IMP and will continue to undergo select study assessments.  The following 
information will be collected: IMP(s) administration, IMP-related AEs, and any SAEs. 
Procedures and data collection for patients still receiving isatuximab at the time of the second 
analysis cutoff date will be as follows: 
• 
Clinical Examinations: 
- 
Ongoing related AE(s) and ongoing SAE(s), up to stabilization or resolution, 
- 
New SAE(s), new related AE(s), 
- 
Reason for end of treatment upon isatuximab discontinuation 
• 
ADA:  
If patient is positive for ADA or the sample is inconclusive, additional ADA samples are 
required every month (± 7 days) until sample is negative. 
• 
Administration of isatuximab 
Patients with ongoing related AE(s) and ongoing SAE(s) after treatment discontinuation will be 
followed until stabilization or resolution of the AE/SAE. 
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13 
STATISTICAL CONSIDERATIONS  
13.1 
DETERMINATION OF SAMPLE SIZE  
Phase I part: 
The Phase I part of this study aims to determine the safety and tolerability of isatuximab. It is 
anticipated that up to 6 to 12 evaluable patients will be enrolled. Patient(s) not evaluable for DLT 
will be replaced. 
Phase II part: 
The Phase II part of the study aims to evaluate 33-36 subjects which include the subjects in  
Phase I part at the recommended dose level. Given an assumed true ORR of 28%, the null 
hypothesis ORR ≤10% will be rejected using an exact binomial test at a one-sided alpha of 0.025 
with at least 80% power, if the observed ORR is greater than or equal to 24.2% (ie, 8 responders). 
The sample size calculation was performed using SAS ver. 9.4 SAS/STAT 13.2, power procedure. 
13.2 
PATIENT DESCRIPTION  
13.2.1 Disposition of Patients  
The number of screened patients as well as the number and percentage of patients included in the 
analysis populations defined in Section 13.3 will be provided. Reasons for treatment 
discontinuation will be summarized using the all treated/safety population. 
13.2.2 Protocol Deviations  
All critical or major deviations potentially impacting evaluation of the MTD (Phase I part only), 
efficacy analyses, as well as drug-dispensing irregularities and other major or critical deviations 
will be summarized in tables giving numbers and percentages of patients with deviations, or only 
the listing will be provided. 
13.3 
ANALYSIS POPULATIONS  
13.3.1 All-treated/safety Population  
For both Phase I and Phase II parts of the study, the all treated/safety population will include all 
patients who have given their informed consent and who have received at least one dose (even 
incomplete) of isatuximab. 
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the treatment actually received. 
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13.3.2 Patients Evaluable for DLT Assessment  
The DLT evaluable population is only applicable to the Phase I part of the study. 
The DLT evaluable population is the subset of patients from the all treated population who have 
completed the first cycle which consists of 4 administrations of the IMP, or they discontinued the 
IMP before completion of the first cycle for a DLT. In practice, a “Dose-Limiting Toxicities” 
form should have been filled in at the end of Cycle 1. If there are missing or incomplete data that 
influence the evaluation of DLT, the patient will not be evaluable for DLT. Patients excluded 
from this population will be replaced. 
13.3.3 Pharmacokinetic Population  
The PK and CD38 receptor density analysis will be performed on the all treated/safety population 
who have a PK parameter. 
13.3.4 Activity/efficacy Population  
The exploratory analysis will be performed on the all treated/safety population who have 
evaluable  data. 
13.4 
STATISTICAL METHODS  
The statistical methods defined in this section will be used for the analysis of the data from the 
Phase I and Phase II parts, unless otherwise specified. Data from each phase will be analyzed and 
reported separately except efficacy evaluation in Phase II part (see Section 6.7.2). Summary tables 
will be presented by dose levels (when appropriate) and overall in Phase I part, unless otherwise 
noted. 
Unless otherwise specified, analyses will be descriptive and performed based on the all treated 
population. 
Continuous data will be summarized using number of available data, mean, standard deviation, 
median, minimum, and maximum. Categorical and ordinal data will be summarized using number 
and percentage of patients. 
13.4.1 Demographics and Baseline Characteristics  
The demographic and baseline characteristics (including age, race, gender, ECOG performance 
status), medical history, cancer diagnosis will be collected at baseline. 
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13.4.2 Extent of Investigational Medicinal Product Exposure  
The extent of investigational product exposure will be assessed and summarized within the all 
treated population. 
The following dose information will be summarized descriptively (N, Mean, Standard deviation, 
Median, Min, and Max). 
• 
Duration of study treatment exposure: defined as day 1 of last cycle date – first dose date + 
28 days, regardless of unplanned intermittent discontinuations. 
• 
Cumulative dose: The cumulative dose is the sum of all doses from first dose to last 
isatuximab administration. 
• 
Actual dose intensity (ADI): defined as the cumulative dose divided by the number of 
weeks on study (duration of study treatment exposure divided by 7). 
• 
Relative dose intensity (RDI): defined as the ratio of the actual dose intensity to the 
planned dose intensity. The RDI is an indicator of the feasibility of the chosen schedule of 
administration. 
The number and its percentage of people who correspond to the following condition will be 
calculated. 
• 
Infusion delay: Within Cycle 1, an infusion is deemed to be delayed if start date of the 
current administration – start date of previous administration is >9 days. For subsequent 
cycles (≥Cycle 2), an infusion is deemed to be delayed if the time interval between 
2 infusions is >17 days (ie. >3 days compared to the theoretical duration between 
2 infusions). 
• 
Dose interruption: administration of isatuximab treatment is temporarily stopped during 
the infusion. 
13.4.3 Prior/concomitant Medication/therapy  
The following parameters regarding prior anticancer will be summarized: 
• 
Prior anticancer treatments: number of prior lines, main anticancer treatments, time from 
completion of last line of treatment to first isatuximab administration (months), best 
response to last line, duration of last line of therapy 
• 
Prior transplant: number (%) of patients with transplant, number of transplants by patients 
• 
Prior surgery: number (%) of patients with any prior surgery related to cancer, type of 
surgery and time from last surgery to first isatuximab administration (months) 
• 
Prior radiotherapy: number (%) of patients with any prior radiotherapy related to cancer, 
intent, location and time from last radiotherapy to first study treatment infusion (months) 
Medications will be summarized by dose level of IMP according to the WHO-DD dictionary, 
considering the first digit of the ATC class (anatomic category) and the first three digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
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summarized. In that summarization, patients will be counted once in each ATC categories 
(anatomic or therapeutic) linked to the medication. 
Medications of specific interest such as antibiotics and hematopoietic growth factors (G-CSF and 
red blood cells transfusion) will be summarized and listed by dose level. Further treatment of 
interest for the analysis and given to the patient after withdrawal from IMP will be listed. 
13.4.4 Analyses of Safety Data  
Analyses of data will be based on the all treated/safety population except DLT evaluation. 
13.4.4.1 Dose-limiting toxicities  
For the Phase I part of the study, DLTs will be summarized by dose level using DLT evaluable 
population. Details will be provided (characteristics of DLTs) by patient. 
13.4.4.2 Analyses of adverse events  
Adverse events will be assessed according to NCI-CTCAE ver. 4.03 from the time of informed 
consent is signed until at least 30 days after the last IMP administration. AEs will be classified by 
System Organ Class/preferred term according to the latest available version of MedDRA 
dictionary. 
Definitions 
• 
Period of observation: The observation period will be divided into three segments: 
pre-treatment, on-treatment and post-treatment.  
• 
The pre-treatment period is defined as the time from when the patients give informed 
consent to the start of IMP.  
• 
The on-treatment period is defined as the time from the first dose of IMP up to 30 days 
after the last dose of IMP.  
• 
The post-treatment period is defined as the time starting 31 days after the last dose of IMP 
to the study closure. 
Pre-treatment AEs are defined as any AE during the pre-treatment period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed, worsened (according to the 
Investigator’s opinion) or became serious during the on-treatment phase. 
Post-treatment AEs are defined as AEs that are reported during the post-treatment period. 
The grade and cycle will be taken into account in the summary. For patients with multiple 
occurrences of the same PT, the maximum grade is used. The denominator used for the summary 
by cycle is the total number of cycles administered in dose level. For a given PT, a patient 
contributes 1 to the numerator for each cycle in which an episode occurred. 
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The primary focus of AE reporting will be on TEAEs. Pre- and post-treatment AEs will be 
described separately. 
Adverse event incidence tables will present for each dose level, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the number of patients in the all treated population. 
The table of all TEAEs presented by system organ class (SOC) and preferred terms (PT) sorted by 
internationally agreed order in SOC and descending order of that frequency in the pooled dose in 
PT (in case of the same frequency, then alphabet order) unless otherwise specified. 
The following TEAE summaries will be generated: 
Overview of TEAEs, summarizing number (%) of patients with any 
• 
TEAEs 
• 
Any Grade 3-4 TEAEs 
• 
Drug-related TEAEs 
• 
Drug-related TEAEs of Grade 3-4 
• 
Serious TEAEs 
• 
TEAEs with a fatal outcome 
• 
TEAEs leading to discontinuation 
• 
DLT 
• 
AESI 
• 
AESI of Grade 3-4 
The following frequency distribution of AEs (incidence tables) will be provided for the safety 
population: 
• 
All TEAEs by SOC and PT and worst NCI-CTCAE grade. 
The same analysis will be performed for drug-related TEAEs, TEAEs leading to discontinuation, 
serious TEAEs, TEAEs with a fatal outcome, and drug-related SAEs occurred during the post 
treatment dosing period. 
13.4.4.3 Deaths  
A listing of deaths will be provided. 
13.4.4.4 Clinical laboratory evaluations  
For patients with multiple occurrences of the same laboratory variable during the on treatment 
period, the maximum grade (worst) per patient and/or per cycle will be used. The denominator 
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used for the summary by cycle is the total number of cycles administered. For a given laboratory 
variable, a patient contributes 1 to the numerator for each cycle in which an episode occurred. An 
episode occurs during a cycle, if the date of sampling is on or after the first day of the cycle, but 
prior to the first day of the next cycle. Hematological and clinical biochemistry toxicities will be 
assessed from laboratory test parameters. Each test result will be graded by NCI-CTCAE ver. 
4.03. The number of patients with abnormal lab tests at baseline will be presented by grade. The 
frequency of patients and/or cycles in each grade of lab tests during on-treatment will be 
summarized (similar analysis will be performed based on data recorded at Cycle 1). When 
appropriate, the summary table will present the frequency of patients and/or cycles with any grade 
of abnormal laboratory tests and with Grade 3-4 of abnormal laboratory tests. 
13.4.4.5 Vital signs  
The descriptive statistics (including mean, median, SD, minimum and maximum) of all vital 
signs’ variables (raw data and changes from baseline) will be calculated for each visit or study 
endpoint (baseline, each post baseline time point, last on treatment value and/or worst value) by 
dosing levels. 
13.4.4.6 Analyses of other safety variables  
Not applicable. 
13.4.5 Analyses of Pharmacokinetic Variables  
Pharmacokinetic parameters of isatuximab will be summarized by descriptive statistics (such as 
mean, geometric mean, median, standard deviation, SEM, CV, minimum, and maximum) under 
the responsibility of Drug Disposition, Disposition, Safety and Animal Research, Sanofi. 
Individual plasma concentrations and PK parameters of isatuximab will be tabulated with standard 
descriptive statistics. Individual and mean profiles will be presented graphically. 
The relationship between dose and exposure will be investigated, using analysis of variance. 
13.4.6 Analysis of Anti-drug Antibody  
The ADA will be summarized by study visits. 
13.4.7 Analysis of CD38 Receptor Density  
The CD38 receptor density will be summarized by study visits for Phase I and Phase II. 
13.4.8 Analyses of Efficacy Variables  
All efficacy analyses will be performed using the all treated/safety population. (see Section 9.3.1) 
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13.4.8.1 Efficacy endpoints for Phase I part of the study  
Best overall response, OS, PFS, TTP, and DOR will be listed along with relevant patient/disease 
characteristics.  
13.4.8.2 Analysis of primary efficacy endpoint for Phase I (Recommended dose level) and 
Phase II part of the study  
Analysis of efficacy endpoint will be performed on all patients who received at least one dose of 
recommended dose across Phase I and II part: 
ORR and the 95% two-sided confidence interval will be computed using Clopper-Pearson 
method. The null hypothesis that the true response rate (ORR) is <10% will be tested using a one-
sided exact binomial test with a significance level of 0.025. 
13.4.8.3 Analysis of secondary efficacy endpoint for Phase II part of the study  
The CBR will be analyzed using the same method as the primary efficacy analysis of ORR. The 
DOR, TTP, PFS and OS will be analyzed using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the 25th, 50th and 75th percentiles and the 95% confidence intervals will also be 
computed. The Kaplan-Meier curves will be plotted. 
13.4.8.4 Analysis of the other exploratory endpoints  
The same analysis will be applied in Phase I and Phase II part. The exploratory endpoints and the 
relationship to clinical outcomes will be analyzed with exploratory manner. 
13.5 
INTERIM ANALYSIS  
No interim analysis is planned. 
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14 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator(s), in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, the International Conference on Harmonisation (ICH) guidelines for Good Clinical 
Practice (GCP), all applicable laws, rules, and regulations. 
Information regarding the clinical trial 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.  
14.2 
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 study, including the written information giving approval/favorable opinion 
by the IRB.  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 trial, the written informed consent form should be 
signed, with the name of the patient filled in and personally dated by the patient 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. 
The 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 IRB for 
approval/favorable opinion. 
The Investigator, or a person designated by the Investigator, should fully inform the patient of all 
pertinent aspects of the clinical trial. All participants should be informed to the fullest extent 
possible about the study in terms they are able to understand. 
14.3 
INSTITUTIONAL REVIEW BOARD  
As required by local regulation, the Investigator must submit this clinical trial protocol to the 
appropriate IRB, 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 composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
CV, etc.) and the date of the review should be clearly stated on the written IRB approval/favorable 
opinion. 
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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 trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB should be informed as soon as possible.  
It 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 will be sent to the IRB. 
A progress report will be sent to the IRB at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial. 
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15 
STUDY MONITORING  
15.1 
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 e-CRF, discrepancy resolution form [DRF], or other appropriate 
instrument) in an accurate manner according to the instructions provided and to ensure direct 
access to source documents by the 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. 
15.2 
RESPONSIBILITIES OF SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-CRFs. 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 trial. 
At regular intervals during the clinical trial, 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. 
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15.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the Monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allowing the Sponsor’s duly authorized 
personnel, the IRB, and the regulatory authorities to have direct access to original medical records 
which support the data on the CRF (eg, patient's medical file, appointment books, original 
laboratory records). These personnel, bound by professional secrecy, must maintain the 
confidentiality of all personal identity or personal medical information (according to 
confidentiality rules). 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS  
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor to record (according to the Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner.  All e-CRFs 
should be completed in their entirety to ensure accurate interpretation of data.  
Should a correction be made, the corrected information will be entered in the e-CRF 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 e-CRF.  
The computerized handling of the data by the Sponsor when available in the e-CRF may generate 
additional requests (DRF) 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 
e-CRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS  
Procedures shall be employed and controls designed to ensure the confidentiality of electronic 
records.  Such procedures and controls shall include validation of systems to ensure accuracy and 
reliability, ability to generate accurate and complete copies of records, protection of records to 
enable retrieval, use of secure, computer-generated, time-stamped entries, use of operational 
system checks, use of device checks to determine validity of source data input, determination that 
person who develop, maintain, or use such systems have adequate education and training, the 
establishment and adherence of written policies to deter record falsification, the use of appropriate 
controls over systems documentation including the distribution of or use of documentation for 
system operation and maintenance, and revision and change control procedures which document 
time-sequenced development and modifications of systems documentation. 
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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16 
ADDITIONAL REQUIREMENTS  
16.1 
CURRICULUM VITAE  
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-Investigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
16.2 
RECORD RETENTION IN STUDY SITES(S)  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
It is recommended that the Investigator retain the study documents at least 15 years after the 
completion or discontinuation of the clinical trial. 
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 trial 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. 
16.3 
CONFIDENTIALITY  
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the e-CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, 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 
IRB is expressly permitted, the IRB 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 trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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16.4 
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 regarding 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 trial. 
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. 
16.5 
DATA PROTECTION  
• 
The patient's personal data, which may be 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 the 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. 
 
Subject race or ethnicity ("Asian/Oriental, others") will be collected in this study because these 
data are required by the PMDA. 
16.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
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 as required by applicable law.  An 
insurance certificate will be provided to the IRBs or regulatory authorities in countries requiring 
this document. 
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16.7 
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/she 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. 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
16.8.1 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 IMP 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 by the Investigator or Subinvestigator, or delegated staff with any 
provision of the clinical trial protocol, or breach of any applicable laws, regulations, or 
ICH GCP guidelines; 
• 
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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16.8.2 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 trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB and regulatory authorities should be informed according 
to applicable regulatory requirements. 
16.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to Investigator. 
When the data from all investigational sites have been fully analyzed by the Sponsor, the latter 
will communicate the results of the clinical trial to the Investigator(s). 
16.10 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 his 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.  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 of 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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17 
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 of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB of an amendment, except where necessary to eliminate an immediate hazard(s) to 
clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial.  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 prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form.  The 
Investigator must receive an IRB 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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18 
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 Tcell 
lineage. Proc Natl Acad Sci U S A. 1980;77(3):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(5136):1056-9. 
4. Goldmacher VS, Bourret LA, Levine BA, Rasmussen RA, Pourshadi M, Lambert JM, et al. 
Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma. Blood. 
1994;84(9):3017-25. 
5. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 
cases of multiple myeloma. Am J Clin Pathol. 2004;121(4):482-8. 
6. Deckert, et al. Clin Cancer Res 2014;20:4574–83. 
7. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860-1873. 
8. Center for Cancer Control and Information Sevice. Cancer statistics graph database URL: 
http://gdb.ganjoho.jp/graph_db/gdb1?smTypes=26 
9. Terpos E, Rahemtulla A, Dimopoulos MA. Current treatment options for myeloma. Expert 
Opin Pharmacother. 2005; 6(7):1127-42. 
10. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. 
International Myeloma Working Group consensus statement for the management, treatment 
and supportive care of patients with myeloma not eligible for standard autologous stem-cell 
transplantation. J Clin Oncol. 2014;32(6):587-600. 
11. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform 
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. 
Blood. 2011 May 5;117(18):4691-5. 
12. Thomas G. Martin, Karl Hsu, et al. A phase I trial of SAR650984, a CD38 monoclonal 
antibody, in relapsed or refractory multiple myeloma. J Clin Oncol 32:5s, 2014 (suppl; abstr 
8532) 
13. Martin III TG, Strickland SA, MSCI, Glenn M, Zheng W, Daskalakis N, et al. SAR650984, a 
CD38 Monoclonal Antibody In Patients With Selected CD38+ Hematological Malignancies- 
Data From a Dose-Escalation Phase I Study. ASH-Hem-2013 2013; abstr. 284. 
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14. David S. Siegel, Thomas Martin, Michael Wang et al. A phase 2 study of single-agent 
carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. 
Blood. 2012 Oct 4;120(14):2817-25. 
15. NCI-CTC Version 4.03 reference. Accessible through the NCI website. Available from URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. [Accessed December 2014]. 
16. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine 
in Japan. Am J Kidney Dis. 2009 Jun;53(6):982-92. 
 
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19 
APPENDICES  
Appendix A 
ECOG Performance Status Scale  
 
Performance 
Status 
Description 
0 
Normal, fully functional 
1 
Fatigue without significant decrease in daily activity 
2 
Fatigue with significant impairment of daily activities or bedrest <50% of waking hours 
3 
Bedrest/sitting>50% of waking hours 
4 
Bedridden or unable to care for self 
 
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Appendix B 
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
Refer to NCI CTC AE v.4.03 (15) in the Study Reference Manual, or online at the following NCI 
website: http://ctep.cancer.gov/reporting/ctc.html 
• 
Toxicity grade should reflect the most severe degree occurring during the evaluated 
period, not an average. 
• 
When 2 criteria are available for similar toxicities, the one resulting in the more severe 
grade should be used. 
• 
The evaluator must attempt to discriminate between disease/treatment and related 
signs/symptoms. 
• 
An accurate baseline prior to therapy is essential. 
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Appendix C 
IMWG Response Criteria  
Disease response will be assessed using the updated International Myeloma Working Group 
Response Criteria (IMWG)(10).  
A confirmation assessment within 4 weeks (±3 days) for disease response evaluation assessments 
is required in this protocol, including MR. 
Table 9 - International Myeloma Working Group Response Criteria  
Response 
IMWG criteria 
sCR 
CR as defined below plus:  
• Normal FLC ratio and  
• Absence of clonal cells in bone marrow by immunohistochemistry or 2 – 4 color flow cytometry 
CR 
• Negative immunofixation on the serum and urine and  
• Disappearance of any soft tissue plasmacytomas and  
• <5% plasma cells in bone marrow.  
• In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is required. 
VGPR 
• Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 
• ≥90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h. 
• In patients with only FLC disease, >90% decrease in the difference between involved and uninvolved FLC 
levels is required. 
PR 
• ≥50% reduction of serum M-protein and reduction in 24 hours urinary M protein by ≥90% or to <200 mg/24 
h 
• If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved 
and uninvolved FLC levels is required in place of the M-protein criteria 
• If serum and urine M-protein are not measurable, and serum free light assay is also not measureable,  
≥ 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma 
cell percentage was ≥30% 
• In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue 
plasmacytomas is also required 
SD 
• Not meeting criteria for CR, VGPR, PR or progressive disease 
PD 
Increase of ≥25% from lowest response value in any one of the following: 
• Serum M-component (the absolute increase must be ≥0.5 g/dL) and/or  
• Urine M-component (the absolute increase must be ≥200 mg/24 h) and/or  
• Only in patients without measurable serum and urine M-protein, the difference between involved and 
uninvolved FLC levels. The absolute increase must be >10 mg/dL 
• Only in patients without measurable serum and urine M-protein and without measurable disease by FLC 
levels, bone marrow plasma cell percentage (absolute % must be ≥10%)  
• Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of 
existing bone lesions or soft tissue plasmacytomas 
• Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the 
plasma cell proliferative disorder 
 
All response categories (CR, sCR, VGPR, PR and PD) require two consecutive assessments made 
at any time before the institution of any new therapy; complete response and PR and SD 
categories also require no known evidence of progressive or new bone lesions if radiographic 
studies were performed.  VGPR and CR categories require serum and urine studies regardless of 
whether disease at baseline was measurable in serum, urine both or either.  Radiographic studies 
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are not required to satisfy these response requirements. Bone marrow assessments need not be 
confirmed.  For progressive disease, serum M-component increases of ≥1 g/dL are sufficient to 
define response if starting M-component is ≥5 g/dL. 
IMWG clarification for coding PD:  Clarified that Bone marrow criteria for PD are to be used 
only in patients without measurable disease by M protein and by FLC levels.  Clarified that 25% 
increase refers to M protein, FLC, and bone marrow results and does not refer to bone lesions, soft 
tissue plasmacytomas or hypercalcemia.  Note the lowest response value does not need to be a 
confirmed value. 
Table 10 - Additional response criteria for specific disease states  
Minor/ minimal response( MR) in 
patients with relapsed and 
refractory myeloma adapted 
from the EMBT criteria 
≥25% but ≤49% reduction of serum M protein and reduction in 24 hour urine M protein by 
50 – 89%, which still exceeds 200 mg/24 hrs. 
In addition to above; if present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytomas is also required. 
No increase in size or number of lytic bone lesions (development of compression fractures 
does not exclude response). 
Immunophenotypic CR 
Stringent CR plus 
Absence of phenotypic aberrant PC (clonal) in bone marrow with a minimum of one million 
of total BM cells analyzed by miltiparamtric flow cytometry (with ≥4 colors) 
Molecular CR 
Stringent CR plus negative ASO-PCR (sensitivity 10-5) 
 
 
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Appendix D 
Definition of Line of Therapy  
A line of therapy is defined as one or more cycles of a planned treatment program. This may 
consist of one or more planned cycles of single-agent therapy or combination therapy, as well as a 
sequence of treatments administered in a planned manner. For example, a planned treatment 
approach of induction therapy followed by autologous stem cell transplantation, followed by 
maintenance is considered one line of therapy. A new line of therapy starts when a planned course 
of therapy is modified to include other treatment agents (alone or in combination) as a result of 
disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period 
of observation off therapy is interrupted by a need for additional treatment for the disease. (11) 
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Appendix E 
Definition of Relapsed and Refractory Myeloma  
Refractory Myeloma: 
Refractory myeloma is defined as disease that is non-responsive (failure to achieve minimal 
response or develop PD while on therapy) while on primary or salvage therapy, or progresses 
within 60 days of last therapy.  There are 2 categories of refractory myeloma. 
• 
Relapsed and refractory myeloma: 
Relapsed and refractory myeloma is defined as disease that is non-responsive while on 
salvage therapy or progresses within 60 days of last therapy in patients who have achieved 
minimal response or better at some point previously to then progressing in their disease 
course. 
• 
Primary refractory myeloma: 
Refractory myeloma is defined as disease that is non-responsive in patients who have 
never achieved minimal response or better with any therapy. It includes patients who never 
achieve MR or better in whom there is no significant change in M protein and no evidence 
of clinical progression; as well as primary refractory, progressive disease where patients 
meet criteria for true progressive disease. 
Relapsed myeloma: 
Relapsed myeloma is defined as previously treated myeloma which progresses and requires the 
initiation of salvage therapy but does not meet the criteria for either primary refractory myeloma 
or relapsed and refractory myeloma. (11) 
 
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Appendix F 
Staging Criteria  
Table 11 - Staging criteria for multiple myeloma  
 
*  There are two categories for Stage II, 
- 
Serum β2 – microglobulin <3.5 mg/L and serum albumin <3.5 g/dL. 
- 
Serum β2 – microglobulin 3.5 mg/L to <5.5 mg/L irrespective of the serum albumin. 
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Appendix G 
Definitions of Infusion Associated Reactions (IARs)  
Table 12 - Types of infusion associated reactionsa  
 
Anaphylaxis 
Acute coronary syndrome 
Cytokine release syndrome 
Drug hypersensitivity 
Infusion related reaction 
a This list is not intended to be exhaustive 
 
Table 13 - Symptoms typically associated with infusion associated reactionsa  
 
Abdominal pain 
Apnoea 
Bronchospasm 
Chest discomfort 
Chest tightness  
Chills 
Cough 
Dizziness 
Dysgeusia 
Dyspnea 
Feeling hot 
Flushing 
Headache 
Head discomfort 
Hoarseness  
Hot flush 
Hypertensive crisis 
Hypoxia 
Influenza like illness  
Injection site pain 
Lacrimation increased 
Laryngospasm 
Myalgia  
Nasal congestion 
Nausea 
Pruritus 
Pyrexia 
Respiratory distress 
Rhinitis  
Rhinorrhoea 
Stridor  
Tachycardia  
Throat irritation 
Tracheal stenosis 
Tremor 
Urticaria 
Vision blurred 
Vomiting 
Wheezing 
a This list is not intended to be exhaustive 
 
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Appendix H 
Revised equations for estimated GFR in Japanese  
eGFR (mL/min/1.73 m2) = 194 x Serum creatinine-1.094 x Age-0.287 x 0.739 (if female). (16) 
Web site of Japan Association of Chronic Kidney Disease Initiative: 
http://j-ckdi.jp/ckd/check.html 
 
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TED14095 - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 117 
Appendix J 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Clinical Trial Summary. 
AMENDED PROTOCOL 04 (14-Dec-2018) 
OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of the second analysis is to obtain PFS and OS by monotherapy from mature data in 
Japanese patients. However, it was found only two events of OS in phase 2 at the first analysis, so 
12 months would not be enough to observe median of OS. That median of OS in 20mg/kg arm in 
TED10893 P2S1 was 18.1 months. Therefore, second cut-off will be postponed from 
approximately 12 months to approximately 20 months. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
NAMES AND 
ADDRESSES OF 
To delete information 
These information are provided in 
CTP attachment. 
CLINICAL TRIAL 
SUMMARY, 6.7.1 
Duration of Study 
Participation for Each 
Patient 
DURATION OF STUDY PERIOD (per 
patient) 
To add as follow; 
Patients with PR or better who come off 
treatment for reasons other than 
progression of disease will be followed 
for disease assessment every 4 weeks 
until progression or initiation of 
subsequent therapy, the second analysis 
cutoff date, whichever comes first. 
To clarify follow-up assessment. 
CLINICAL TRIAL 
SUMMARY, 6.7.2 
Determination of End of 
Clinical Trial (all 
patients) 
STATISTICAL CONSIDERATIONS 
Planned database lock - the second 
cutoff date: 20 months 
To get enough period for 
observation of median of OS. 
1.4 STUDY 
FLOWCHART - 
PHASE I PART 
To add a new footnote as follow; 
Subsequent Cycles 3, 35 
To clarify assesment items post 
second analysis cut-off period. 
1.5 STUDY 
FLOWCHART - 
PHASE II PART 
To add a new footnote as follow; 
Subsequent Cycles 3, 35 
To clarify assesment items post 
second analysis cut-off period. 
1.6 FOOTNOTES FOR 
STUDY 
FLOWCHARTS 
33 To add as follow;“or second cut-off 
date, whichever comes first.” 
To clarify study duration. 
 
To add as follow; 
35. Post second analysis cut-off period, 
only AE/SAE reporting will be collected 
To clarify assesment items post 
second analysis cut-off period. 
1.7 PK FLOW CHART - 
PHASE I PART 
To add a new footnote as follow; 
Subsequent Cyclesg 
To clarify assesment items post 
second analysis cut-off period. 
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Amended Clinical Trial Protocol No. 05  
15-Jul-2020 
TED14095 - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 118 
Section # and Name 
Description of Change 
Brief Rationale 
 
To add as follow; 
g Post second analysis cut-off period, 
only ADA samples will be collected. 
To clarify assesment items post 
second analysis cut-off period. 
1.8 PK FLOW CHART - 
PHASE II PART 
To add a new footnote as follow; 
Subsequent Cyclesf 
To clarify assesment items post 
second analysis cut-off period. 
 
To add as follow; 
f Post second analysis cut-off period, 
only ADA samples will be collected. 
To clarify assesment items post 
second analysis cut-off period. 
12.5 
FOLLOW-UP 
VISIT (TO BE 
PERFORMED 60 
DAYS (+/- 7 DAYS) 
AFTER THE LAST 
ADMINISTRATION OF 
THE INVESTIGATION 
MEDICINAL 
PRODUCT) 
To add disease assessment section with 
the sentence as follow; 
Disease assessments during follow-up 
period are only required for patients with 
PR or better who have discontinued 
study treatment for reasons other than 
disease progression and have not yet 
started treatment with another anti-
cancer therapy. Disease assessments 
will be done up to PD, initiation of further 
anti cancer therapy or second cut-off 
date, whichever comes first. 
To delete  
Disease assessments not required once 
patient starts treatment with another anti
cancer therapy 
To clarify disease assesment on 
follow-up visit. 
12.6 PERIOD POST 60 
DAYS FOLLOW-UP 
PERIOD 
Patients will also be followed for survival 
status approximately every 3 months 
from the date of last IMP administration 
until death or second cutoff date, 
whichever comes first. 
To clarify study duration. 
12.7 POST SECOND 
ANALYSIS CUT-OFF 
PERIOD 
To delete as follow; 
Laboratory Assessments: 
Urine Pregnancy Test 
•Disease Assessment: 
Myeloma specific Lab Tests:  
M protein quantification (serum and 24
hours urine) 
Serum β2 microglobulin to be performed 
if clinically indicated 
Immunoglobulins: IgG, IgA and IgM (IgD 
or IgE test to be performed if positive at 
baseline) 
Corrected serum calcium 
Serum and urine immunofixation and 
free light chain to be performed to 
confirm a CR and as clinically indicated. 
Extramedullary Disease (approximately 
every 12 weeks): only required if 
In post second analysis cut-off 
period, it is modified to do only 
safety observation. 
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Amended Clinical Trial Protocol No. 05  
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TED14095 - isatuximab 
Version number: 1 
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Page 119 
Section # and Name 
Description of Change 
Brief Rationale 
clinically indicated. No need to send 
images to the committee. 
Skeletal survey:  only required if 
clinically indicated. 
Appendix J Protocol 
amendment history 
Added an Appendix with details of past 
protocol amendment changes as per the 
new template requirements 
Added this Appendix as per the 
new template requirements 
 
Amended Clinical Trial Protocol 3 based on Protocol Amendment 03: [12-Oct-2017] 
Rationale for the amendment (03) 
Section # and Name 
Description of Change 
Brief Rationale 
CLINICAL TRIAL 
SUMMARY, 1.4 STUDY 
FLOWCHART - PHASE I 
PART, 1.5 STUDY 
FLOWCHART - PHASE II 
PART, 1.6 FOOTNOTES 
FOR STUDY 
FLOWCHARTS: 9 and 10, 
1.7, 1.8, 3 LIST OF 
ABBREVIATIONS, 6.6.1 
Management of Potential 
Infusion Associated 
Reactions (IARs) , 9.1.9 
Other Clinical 
Assessments, 12.3.1 Day 
1 of Each Cycle, 
Removed cytokines from safety evaluation 
Following isatuximab administration 
(TED10893, phase 1), higher cytokine levels 
for IL-1, IL-6, TNF-α, and IFN γ were noted 
as compared to baseline: the median peak 
values (defined as the highest value during 
the on-treatment period) of IFN-γ, IL-1β, IL-6, 
and TNF-α were 0.44, 0.34, 6.48, and 24.66 
pg/mL, respectively, with median relative 
change from baseline ranging from 6% to 
184% across the 4 cytokines with no evident 
dose dependency. For each cytokine, the 
median of the peak value was overall similar 
for patients who never experienced an IAR 
during the on-treatment and those who 
developed at least one IAR during the on-
treatment period. Therefore, no association 
between the transient cytokine increases and 
the occurrence of IARs could be 
demonstrated. 
CLINICAL TRIAL 
SUMMARY, 1.6 
FOOTNOTES FOR 
STUDY FLOWCHARTS: 
9 , 6.6.1 Management of 
Potential Infusion 
Associated Reactions 
(IARs), 12.3.1 Day 1 of 
Each Cycle 
Removed markers of complement and serum 
tryptase from safety evaluation 
Regarding complement activation (C3a, C4, 
CH50) and serum tryptase measurement, the 
samples are collected only in case of IARs do 
not allow to perform any interpretation and 
reach a conclusive outcome. 
CLINICAL TRIAL 
SUMMARY, 7.3 
EXCLUSION CRITERIA 
E 18. Any medical conditions that, in the 
Investigator’s opinion, would impose excessive 
risk to the patient (eg, poorly controlled diabetes 
requiring insulin treatment or poorly controlled 
hypotension). 
To clarify exclusion criteria. 
1.6 FOOTNOTES FOR 
STUDY FLOWCHARTS, 
ADA (Anti-Drug Antibodies) is performed on Day 
1 of cycle up to 10 cycles. If ADA is positive at 
To modify according to Amendment of the 
global studies. 
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Amended Clinical Trial Protocol No. 05  
15-Jul-2020 
TED14095 - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 120 
Section # and Name 
Description of Change 
Brief Rationale 
1.7 PK FLOW CHART- 
PHASE I PART, 1.8 PK 
FLOW CHART- PHASE II 
PART, 9.1.8 
Immunogenicity, 12.3.1 
Day 1 of Each Cycle 
Cycle 10, one additional sampling for ADA 
evaluation should be collected 3 months later. 
No further ADA will be collected, even if the 3-
month sample is positive. 
8.3 PRE-MEDICATION 
Patients who do not experience an IAR during 
the first 4 consecutive administrations of 
isatuximab may have the need for subsequent 
pre-medication reconsidered at the 
investigator’s discretion in consultation with the 
Sponsor. 
To clarify the condition for reconsideration of 
pe-medication. 
In addition, other minor changes were made in the document. 
 
Amended Clinical Trial Protocol 02 based on Protocol Amendment 02 [27-Jan-
2017] 
Overall Rationale for the Amendment 
Rationale for the amendment (02) 
Section # and Name 
Description of Change 
Brief Rationale 
CLINICAL TRIAL 
SUMMARY, 8.1.1 
Pharmaceutical Form, 
8.1.3 Preparation, 
Reconstitution and 
Administration of 
isatuximab 
Addition to the dose preparation method of the 
IMP as “5% dextrose solution”. 
To harmonize the dose preparation method 
of the IMP with most current pharmacy 
manual. 
The data of 5% dextrose as an IV diluent 
become available. 
6.6.1 Management of 
Potential Infusion 
Associated Reactions 
(IARs) 
Patient(s) should routinely receive pre-
medications prior to isatuximab infusion as 
detailed in Section 8.3 to reduce the risk and 
severity of IARs commonly observed with 
monoclonal antibodies. Infusion associated 
reactions (NCI-CTCAE, version 4.03 term 
Infusion related reaction), including 
“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. 
To clarify the definition of infusion associated 
reaction. 
Appendix I CD38 blood 
test interference guideline 
AABB2016 
To add information letter. 
To inform that CD38 monoclonal antibodies 
interferers with blood bank serologic tests. 
In addition, other minor changes were made in the document. 
 
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15-Jul-2020 
TED14095 - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 121 
Amended Clinical Trial Protocol 01 based on Protocol Amendment01: [13-May-2016] 
Rationale for the amendment (01) 
Section # and Name 
Description of Change 
Brief Rationale 
CLINICAL TRIAL 
SUMMARY; 5.3 
Exploratory Objectives, 
9.4.3 Exploratory 
Biomarker Studies. 
Exploratory objective change due to deletion of 
tumor cell genomics testing 
The analysis of tumor cell genomics is 
terminated worldwide due to difficult sample 
collection from bone marrow and 
deprioritization of CD38 expression as 
predictive biomarker. Preliminary analysis in 
TED10893 Phase 2 Stage 1 did not show 
clear predictive value of CD38 mRNA. 
CLINICAL TRIAL 
SUMMARY, 7.2 Inclusion 
Criteria 
Change in inclusion criteria #9 due to comply 
with the comments from the local regulatory 
authority (PMDA) regarding contraceptive 
measures and contraception period in the 
protocol 
Added examples of contraceptive measures 
which are available in Japan. 
Deleted uncertain contraceptive measures such 
as “abstinence”.  
Prolonged the contraception period from 12 
weeks to 6 months. 
To comply with PMDA suggestions arose 
during the review period of initial Clinical Trial 
Notification (CTN).  
• 
PMDA suggested to clarify the 
contraceptive measures which are 
available in Japan.  
• 
PMDA suggested to delete uncertain 
method of contraception such as 
“abstinence”.  
• 
PMDA requested to prolong the 
contraception period based on the PK 
data such as half live of isatuximab. 
CLINICAL TRIAL 
SUMMARY, 7.3 Exclusion 
Criteria 
Change in exclusion criteria # 20 due to comply 
with the comment from PMDA regarding 
lactating patients. 
Added when female subjects who stopped 
lactating can re-start. 
To comply with PMDA suggestions arose 
during the review period of initial CTN.  
PMDA suggested to articulate the eligibility 
for female subjects who stopped lactating 
and the washout period allowing re-start of 
lactating. 
CLINICAL TRIAL 
SUMMARY, 1.6 Footnotes 
for Study Flowcharts #9, 
#10, 6.6.1. Management of 
Potential Infusion 
Associated Reactions 
(IARs), 12 Study 
Procedures. 
Change in test items of cytokines assessment. 
Added new test item IL-4 as a new test item for 
cytokines assessment. 
To harmonize standard method of cytokines 
assessment across the ongoing studies. 
CLINICAL TRIAL 
SUMMARY, 9.1.1 Dose-
limiting Toxicities in Phase 
I part 
Change in DLT criteria regarding platelet 
transfusion. 
Due to comply with the comment from PMDA. 
CLINICAL TRIAL 
SUMMARY, 9.2.3 
Bioanalytical Method 
Replaced bioanalytical method of ADA from 
“Bridge ELISA” to “P and A”. 
To harmonize standard bioanalytical method 
across the ongoing studies. 
1.6 Footnotes for Study 
Flowcharts #6, #14 
Addition of anti-CD38 interference with serologic 
testing. 
Added how to deal with anti-CD38 interference 
with serologic testing. 
CD38 monoclonal antibodies can result in 
interference with blood bank serologic tests 
and thereby cause delays in issuing Red 
Blood Cell (RBC) units to patients receiving 
these agents. The AABB Clinical Transfusion 
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Amended Clinical Trial Protocol No. 05  
15-Jul-2020 
TED14095 - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 122 
Section # and Name 
Description of Change 
Brief Rationale 
Medicine Committee has developed a bulletin 
(# 16-02) to provide background information 
and guidance to members regarding anti-
CD38 interference with serologic testing. This 
bulletin will be provided to the investigators 
as a protocol supplemental document. The 
patients treated in the study will receive a 
patient card indicating the treatment with a 
CD38 agent. The protocol also requested to 
the study site to notify its blood bank that the 
patient is receiving an anti- CD38 treatment. 
Direct and indirect coombs tests prior to first 
IMP administration was recommended by 
potential principal investigator of JP red cross 
medical center on April 14th, 2016. 
1.4 Study Flowchart - 
Phase I part, 1.6 
Footnotes for Study 
Flowcharts #7 
Change in recommended hospitalization period. 
The end date of the recommended 
hospitalization during the DLT observation 
period was changed from “Day 8” to “the entire 
day of the 3rd infusion”. 
To comply with PMDA suggestions arose 
during the review period of initial Clinical Trial 
Notification (CTN). 
PMDA suggested to refer the local guideline: 
“Guideline of clinical evaluation method for 
anti-cancer drugs” and consider 
hospitalization during the entire DLT period. 
PMDA accepted to shorten the 
recommended hospitalization period to the 
end of the 3rd infusion which may cover all 
infusion associated reactions (IARs) based 
on the IARs data as of Nov. 6th, 2015 
(presentation of TED10893 at ASH 2015, 
page 10). 
1.4 Study Flowchart - 
Phase I part, 1.5 Study 
Flowchart - Phase II part, 
1.6 Footnotes for Study 
Flowcharts #20. 
Change in Hepatitis B Virus (HBV) test. 
Added HBc-Ab and HBs-Ab test in screening/ 
baseline and monthly HBV-DNA test if history of 
HBV is suspected. 
To comply with PMDA suggestions arose 
during the review period of initial CTN. 
Need to amend the protocol in accordance 
with the local guideline of “hepatitis B caused 
by immunosuppressive drug or chemo 
therapy” which recommends monthly HBV-
DNA if history of HBV infection is suspected. 
1.6 Footnotes for Study 
Flowcharts #21, 22, 12. 
Study Procedures 
Change in disease assessment procedures to 
comply with IMWG 
The disease assessment procedures are 
detailed and frequency of the assessments is 
adjusted based on IMWG criteria. 
To clarify the procedure requiring for efficacy 
evaluation and adjusted the frequency of the 
assessments. 
4.1 Introduction 
Change in introduction of isatuximab 
Added the information of isatuximab is produced 
in CHO cells and using recombinant DNA 
technology. 
To comply with PMDA suggestions arose 
during the review period of initial CTN.  
PMDA suggested adding information on cell 
line and using recombinant DNA technology. 
Other additional minor changes and edits were included in this amendment for the sake of clarity. 
 
VV-CLIN-0514516 5.0


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VV-CLIN-0514516 5.0

SAP_001.pdf: 
16.1.9 Statistical analysis plan
Page 1
NCT02812706


1
3
43
Table of Contents
16.1.9 Statistical analysis plan.....................................................................................................
16.1.9.1 Statistical Analysis Plan for Phase 1.................................................................................
16.1.9.2 Statistical Analysis Plan for Phase 2.................................................................................
Page 2
 


 
 
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 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
 
 
STATISTICAL ANALYSIS PLAN 
A Phase I/ II Study of Isatuximab (Anti-CD38 mAb) administered as a single agent 
in Japanese Patients With Relapsed AND Refractory Multiple Myeloma 
SAR650984-TED14095 (Phase 1) 
STATISTICIAN: 
  
DATE OF ISSUE: 30-Aug-2018 
 
 
Total number of pages: 
39 
(electronic 
 
 
 
2.0)
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives .......................................................................................................................7 
1.2.3 
Exploratory objectives ......................................................................................................................8 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................11 
2.1 
ANALYSIS ENDPOINTS................................................................................................................11 
2.1.1 
Demographic and baseline characteristics ....................................................................................11 
2.1.2 
Prior or concomitant medications (other than anticancer therapies)..............................................13 
2.1.3 
Efficacy endpoints ..........................................................................................................................14 
2.1.4 
Safety endpoints.............................................................................................................................15 
2.1.4.1 
Adverse events variables ...............................................................................................................15 
2.1.4.2 
Deaths............................................................................................................................................16 
2.1.4.3 
Laboratory safety variables ............................................................................................................16 
2.1.4.4 
Vital signs variables........................................................................................................................17 
2.1.4.5 
Electrocardiogram variables...........................................................................................................17 
2.1.4.6 
Other safety endpoints ...................................................................................................................18 
2.1.5 
Pharmacokinetic variables .............................................................................................................18 
2.1.6 
CD38 Receptor density ..................................................................................................................18 
2.1.7 
Immune response ..........................................................................................................................18 
2.1.8 
Pharmacodynamic/genomics endpoints ........................................................................................20 
2.1.9 
Quality-of-life endpoints..................................................................................................................20 
(electronic 
 
 
 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 3 
2.1.10 
Health economic endpoints............................................................................................................20 
2.1.11 
Exploratory endpoints.....................................................................................................................20 
2.1.12 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................20 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................20 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................21 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................21 
2.3.1 
All treated/safety populations .........................................................................................................21 
2.3.2 
DLT evaluable population...............................................................................................................21 
2.3.3 
Pharmacokinetic population...........................................................................................................21 
2.3.4 
ADA population ..............................................................................................................................22 
2.4 
STATISTICAL METHODS .............................................................................................................22 
2.4.1 
Demographics and baseline characteristics ..................................................................................22 
2.4.2 
Prior or concomitant medications (other than anticancer therapies)..............................................22 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................22 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................25 
2.4.5 
Analyses of safety data ..................................................................................................................25 
2.4.5.1 
Analyses of adverse events ...........................................................................................................25 
2.4.5.2 
Deaths............................................................................................................................................27 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................28 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................28 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................28 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................28 
2.4.6 
Analyses of pharmacokinetic, CD38 receptor density and immune response...............................29 
2.4.6.1 
Pharmacokinetic variables .............................................................................................................29 
2.4.6.2 
CD38 receptor density....................................................................................................................29 
2.4.6.3 
Immune response ..........................................................................................................................29 
2.4.7 
Analyses of quality of life/health economics variables ...................................................................29 
2.4.8 
Analyses of exploratory variables...................................................................................................30 
2.4.9 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................30 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................30 
2.5.1 
General conventions ......................................................................................................................30 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................30 
2.5.3 
Missing data ...................................................................................................................................30 
2.5.4 
Windows for time points.................................................................................................................32 
2.5.5 
Unscheduled visits .........................................................................................................................32 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................32 
(electronic 
 
 
 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 4 
2.5.7 
Statistical technical issues .............................................................................................................32 
3 
INTERIM ANALYSIS .....................................................................................................................33 
4 
DATABASE LOCK ........................................................................................................................34 
5 
SOFTWARE DOCUMENTATION..................................................................................................35 
6 
REFERENCES...............................................................................................................................36 
7 
LIST OF APPENDICES .................................................................................................................37 
APPENDIX A POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......................38 
APPENDIX B SPONSOR GENERIC RANGES..........................................................................................39 
(electronic 
 
 
 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibody 
ADI: 
actual dose intensity 
AESI: 
adverse events of special interest 
ATC: 
anatomical therapeutic chemical 
BOR: 
best overall response 
CR: 
complete response 
CT: 
computed tomography 
DLT: 
dose limiting toxicity 
DOR: 
duration of response 
ECOG: 
eastern cooperative oncology group 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
HLGT: 
high level group term 
HLT: 
high level term 
IAC: 
independent adjudication committee 
IAR: 
infusion associated reaction 
IMP: 
investigational medicinal product 
IMWG: 
international myeloma working group 
ISS: 
international staging system 
IV: 
intravenous 
MM: 
multiple myeloma 
MR: 
minimal response 
MRD: 
minimal residual disease 
MRI: 
magnetic resonance imaging 
MUGA: 
multigated acquisition 
NCI-CTCAE: 
national cancer institute common terminology criteria for adverse event 
OS: 
overall survival 
PCSA: 
Potentially Clinically Significant Abnormalities 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PR: 
partial response 
PS: 
performance status 
PT: 
preferred term 
Q2W: 
once every other week 
QW: 
once every week 
RD: 
receptor density 
RDI: 
relative dose intensity 
SAP: 
statistical analysis plan 
SD: 
stable disease 
SOC: 
system organ class 
(electronic 
 
 
 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 6 
TEAE: 
treatment-emergent adverse event 
TTR: 
time to response 
VGPR: 
very good partial response 
 
 
(electronic 
 
 
 
2.0)
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
This is an open-label, single arm, local multi-center study conducted in 2 parts, phase 1 and phase 
2. This statistical analysis plan (SAP) describes the statistical methods to be used for the analyses 
of data collected during the phase 1 part of the study. For the phase 2 part, the SAP is described 
separately. This SAP should be read in conjunction with the study protocol and electronic case 
report form (e-CRF). 
1.1 
STUDY DESIGN AND RANDOMIZATION 
The phase 1 part of TED14095 is a standard 3+3 dose-escalation study of isatuximab administered 
as a single agent as an intravenous (IV) infusion every week (QW) during cycle 1 followed by 
every 2 weeks (Q2W) during subsequent cycles to adult patients with relapsed and refractory 
multiple myeloma (MM). 
In this study, a cycle is basically 28 days. Treatment with isatuximab is to be continued until 
unacceptable adverse event, disease progression, death, withdrawal of patient, or investigator’s 
decision. Dose has two levels, 10 mg/kg and 20 mg/kg. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the phase 1 part of this study is to evaluate safety and tolerability of 
isatuximab in Japanese patients with relapsed and refractory MM. 
1.2.2 Secondary objectives 
Secondary objectives of the phase 1 part of the study are: 
• 
To evaluate the safety including immunogenicity of isatuximab. The severity, frequency 
and incidence of all adverse events will be assessed. 
• 
To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing 
schedule. 
• 
To assess the efficacy using International Myeloma Working Group (IMWG) uniform 
response criteria. 
• 
To assess the relationship between baseline CD38 receptor density (RD) on MM cells and 
efficacy. 
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1.2.3 Exploratory objectives 
The following exploratory objectives will be investigated in the end of phase 2 part of the study. 
• 
To assess minimal residual disease (MRD) in patients achieving Complete Response (CR) 
and correlate with clinical outcome. 
• 
To investigate the relationship of soluble CD38 and parameters of PK and clinical 
response. 
• 
To investigate the relationship between multiple myeloma molecular subtype (as defined 
by cytogenetics/ fluorescence in situ hybridization (FISH)) and parameters of clinical 
response. 
• 
To investigate the relationship between immune genetic determinants, immune phenotype 
and parameters of clinical response. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The phase 1 part of this study aims to determine the safety of isatuximab at the global 
recommended dose. It is anticipated that up to 6 to 12 evaluable patients will be enrolled, 
depending on the toxicity occurrence. Patient(s) not evaluable for Dose Limiting Toxicity (DLT) 
will be replaced. 
1.4 
STUDY PLAN 
Safety evaluations are performed continuously throughout the study and included the following: 
• 
DLTs evaluations 
• 
AEs according to the National Cancer Institute Common Toxicity Criteria for Adverse 
Event (NCI-CTCAE) v. 4.03 grading scale 
• 
Vital signs 
• 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
• 
12 lead electrocardiogram (ECG) or 2-D echocardiogram or Multigated Acquisition 
(MUGA) scan 
• 
Chest X-ray 
• 
Laboratory tests in blood and urine 
• 
Level of human anti-drug antibodies (ADA) 
• 
Cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1-β, IL-4, IL-6, 
interferon-gamma [IFN-γ]), complement activators and tryptase 
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Disease response evaluation for patients is performed every 4 weeks, unless otherwise stated, 
including: 
• 
M-protein quantification (serum and/or 24-hour urine, protein electrophoresis and 
immunoelectrophoresis), serum free light chain (FLC) levels 
• 
Serum β2-microglobulin, quantitative immunoglobulins and serum calcium 
• 
Bone skeletal survey, computed tomography (CT) scan or magnetic resonance imaging 
(MRI) as clinically indicated 
• 
Radiologic imaging (CT/MRI scan) of plasmacytoma 
• 
Survival status 
The following additional evaluation is also performed: 
• 
CD38 RD on bone marrow samples 
PK samples are collected in all patients receiving isatuximab as depicted in the PK study 
flowcharts included in the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). The protocol history table below 
gives the timing, rationale, and key details of major changes to the protocol statistical section. 
Table 1 – protocol amendment statistical changes 
Amendment Number 
Date Approved 
Rationale 
Description of 
statistical chnages 
1 
13-May-2016 
To harmonize the other global 
studies 
Summary of prior anti-cancer 
therapy 
1 
13-May-2016 
To harmonize the other global 
studies 
Overview of TEAEs 
1 
13-May-2016 
To harmonize the other global 
studies 
Deletion of the description in 
“Analyses of Pharmacokinetic 
variables” 
 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
This statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan. Changes also 
incorporated in a protocol amendment are cross-referenced to Table 1. 
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The first patient was enrolled on September 2016. There were no planned interim analyses. 
Table 2 – Statistical analysis plan statistical changes 
SAP version number 
Date approved 
Rationale 
Description of 
statistical changes 
2 
This version 
To harmonize the other global 
studies 
MM characteristics at study 
entry 
2 
This version 
To harmonize the other global 
studies 
Refractory status in prior 
anticancer therapies 
2 
This version 
To harmonize the other global 
studies 
Analyses for infusion 
associated reaction 
2 
This version 
To harmonize the other global 
studies 
Summary for extent of 
exposure and dose 
modification 
2 
This version 
To harmonize the other global 
studies 
Summary of ADA 
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
Unless otherwise specified, the baseline value is defined as the last available value before the first 
isatuximab administration. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are gender (Male, Female), ethnicity (Hispanic or Latino , Not Hispanic or 
Latino, Not reported, and Unknown), race (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific Islander, White, Not reported, Unknown), 
age in years (quantitative and qualitative variable : < 65, [65 - 75) and ≥ 75 years), weight (kg), 
and ECOG PS at baseline. 
Medical or surgical history 
Medical or surgical history other than MM will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version in effect at Sanofi (or the data management vendor) at 
the time of the data base lock. 
MM characteristics at initial diagnosis 
The following MM characteristics at initial diagnosis will be described: time from initial diagnosis 
to first isatuximab administration (in years) and by category (<5 years and ≥5 years), International 
Staging System (ISS) stage, and MM subtype (as collected in the e-CRF). 
MM characteristics at study entry 
The following MM characteristics at study entry will be displayed: derived ISS stage (Table 3), 
measurable paraprotein at baseline (Table 4), plasmacytoma in bone marrow (quantitative results 
and by category: 0, (0 - 5%), [5 - 20%), [20 - 50%), and ≥ 50%), patients with plasmacytomas, 
patients with bone lesions, serum β2-microglobulin level in mg/L (quantitative results and by 
category: < 3.5 mg/L, [3.5 - 5.5 mg/L), ≥ 5.5 mg/L), serum albumin in g/L (quantitative results 
and by category: < 35 g/L and ≥ 35 g/L). 
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Table 3 – ISS staging definition 
Stage 
Definition 
Stage I 
Serum β2-microglobulin <3.5 mg/L and serum albumin ≥ 35 g/L 
Stage II 
serum β2-microglobulin <3.5 mg/L and serum albumin <35 g/L  
or 
 serum β2-microglobulin 3.5 - <5.5 mg/L regardless of serum albumin levels 
Stage III 
Serum β2-microglobulin ≥5.5 mg/L regardless of serum albumin levels 
 
Table 4 – Derivation of measurable paraprotein at study entry 
Measurable paraprotein 
Criteria 
Serum M-Protein 
Serum M-Protein ≥ 0.5 g/dL 
and 
urine M-Protein < 200 mg/24hours or missing 
Urine M-Protein 
Serum M-Protein < 0.5 g/dL or missing 
and 
urine M-Protein ≥ 200 mg/24hours 
Serum M-Protein and Urine M-Protein 
Serum M-Protein ≥ 0.5 g/dL 
and 
urine M-Protein ≥ 200 mg/24hours 
 
 
Molecular subtype at initial diagnosis 
Molecular subtype included cytogenetics analysis by FISH (as collected in the e-CRF). 
Molecular subtype at study entry 
Molecular subtype included cytogenetics analysis by FISH which are 17p deletion, t (4, 14), and t 
(14; 16). High risk group is defined as patients with at least one chromosomal abnormality.  
Prior anticancer therapies 
• 
Prior anticancer treatments: number of prior lines (2, 3, 4, 5, 6, 7 and ≥ 8 and as a 
quantitative variable), main category of drug (i.e., alkylating agent, anthracycline, 
proteasome inhibitor, immunomodulatory drugs others), drug name (i.e., melphalan, 
cyclophosphamide, doxorubicin, lenalidomide, pomalidomide, thalidomide, bortezomib, 
carfilzomib, ixazomib, elotuzumab, and panobinostat), time from completion of last line of 
treatment to first Investigational Medicinal Product (IMP) administration (months), best 
response to last line, duration of last line of therapy. 
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In addition, the refractory status to each anticancer treatment will be derived. A patient is 
considered to be refractory if any of the following conditions are met: 
- 
Progression date and anticancer treatment end date are complete and progression date 
is within (≤) 60 days of anticancer treatment end date (progression date – anticancer 
treatment end date ≤ 60 days). If only the day is missing for either date or both dates, 
and the progression date and anticancer treatment end date corresponds to two 
consecutive months within the same year, then, the patient will be considered 
refractory, otherwise they will be considered not refractory. 
- 
Best overall response is SD or PD. 
- 
Reason for treatment discontinuation is “disease progression” 
• 
Prior transplant: number (%) of patients with transplant, number (%) of transplant by 
patient (1, 2 and ≥3) 
• 
Prior surgery: number (%) of patients with any prior surgery and time from last surgery to 
first IMP administration (months) 
• 
Prior radiotherapy: number (%) of patients with any prior radiotherapy, intent (curative and 
palliative), type (systemic, internal beam, and external beam), and time from last 
radiotherapy to first IMP administration (months) 
Any technical details related to computation, dates, and imputation for missing dates, are 
described in Section 2.5. 
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken within 7 days prior to first dose of IMP, at any time during the treatment 
period, and up to 30 days after the last isatuximab administration are reported in the e-CRF. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version in effect at Sanofi (or the data management vendor) at the time of the data base lock. 
• 
Prior medications are those the patient used prior to first isatuximab administration. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment phase.   
• 
Concomitant medications are any treatments received by the patient concomitantly to 
isatuximab, from first dose to the date of last administration + 30 days. A given medication 
can be classified both as a prior medication and as a concomitant medication.  
Concomitant medications do not include medications started during the post treatment 
period (as defined in the observation period in Section 2.1.4).  
• 
Post treatment medications (excluding post anticancer treatments) are those the patient 
took from 31 days after last isatuximab administration up to the end of the study. 
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Pre-medication 
Patients are to routinely receive pre-medications prior to isatuximab infusion to reduce the 
incidence and severity of hypersensitivity reactions. Pre-medications were defined in the protocol 
as non-IMP(s). The recommended pre-medication agents were: diphenhydramine 25-50 mg IV (or 
equivalent), methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent), 
and acetaminophen 650-1000 mg po 15-30 minutes (but no longer than 60 minutes) prior to 
isatuximab infusion. Analysis of pre-medications will focus on antihistamine, corticosteroids, h2 
blocker, and acetaminophen given (start and stop dates) on the days of isatuximab administrations. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
All efficacy endpoints are defined as secondary objectives. 
Disease assessments are performed every cycle by the Independent Adjudication Committee (IAC) 
using the IMWG criteria. The assessment of “Progressive disease” by the site doctor (collected in 
e-CRF) will not be used for phase 1 in efficacy analysis. 
The following efficacy endpoints will be derived for the phase 1 part of the study. 
Best overall response (BOR): defined as the best sequential response in every cycle’s assessment 
from the start of treatment through the entire study excluding any time point following the start of 
other treatment for MM. The ordering of evaluations from best to worse is: stringent complete 
response (sCR), complete response (CR), very good partial response (VGPR), partial response 
(PR), minimal response (MR), stable disease (SD), progressive disease (PD), not evaluable (NE). 
Confirmation of response is needed. 
Overall survival (OS): defined as the time interval from the date of first study treatment 
administration to death due to any cause. In the absence of the confirmation of death before the 
analysis cutoff date, OS will be censored at the last date the patient is known to be alive or at the 
study cutoff date, whichever is earlier. 
Progression free survival (PFS): defined as the time interval from the date of first study treatment 
administration to the date of the first assessed disease progression or death due to any cause, 
whichever comes first. In the absence of disease progression, death before the analysis cutoff date 
or death before the date of initiation of new anticancer treatment, PFS will be censored at the 
earliest of the date of the last valid assessment not showing disease progression performed before 
initiation of new anticancer treatment or the analysis cutoff date, whichever is earlier. 
Duration of response (DOR): DOR is defined as the time from first response that is subsequently 
confirmed to the first documented tumor progression or death. If progression or death is not 
observed, the date of the last valid disease assessment performed before cutoff date or initiation of 
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a new anticancer treatment will be used. DOR is determined only for patients who have achieved a 
response of ≥ PR and will not be calculated for patients who did not achieve a response. 
Time to response (TTR): TTR is defined as the time from first dose to first response (PR or better) 
that is subsequently confirmed. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data, vital signs, ECG, etc. 
Observation period  
The observation period will be divided into 3 periods: pre-treatment, on-treatment and post-
treatment. 
• 
The pre-treatment period is defined as the time from when the patients give informed 
consent and the start of isatuximab.  
• 
The on-treatment period is defined as the time from first dose of isatuximab up to 30 
days after the last dose of isatuximab. 
• 
The post-treatment period is defined as the time from 31 days after the last dose of 
isatuximab to the study closure. 
2.1.4.1 Adverse events variables 
All adverse events occurring from informed consent signature until at least 30 days after the last 
isatuximab administration and new adverse events related to isatuximab on the post-treatment 
period will be collected in the e-CRF. The severity of AEs will be assessed according to NCI-
CTCAE version 4.03. 
All adverse events (including serious adverse events [SAEs]) will be 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) in effect at Sanofi (or the data management vendor) at the time of the data 
base lock. 
Adverse event observation period  
• 
Pretreatment adverse events are adverse events that developed or worsened or became 
serious during the pre-treatment period. 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the on-treatment period. 
• 
Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period. 
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Adverse events of special interest 
The following AEs are considered adverse events of special interest (AESIs): 
• 
Acute infusion associated reactions (IARs) 
• 
DLTs 
• 
Symptomatic overdose 
• 
Pregnancy occurring in a female patient or in a female partner of a male patient 
Infusion associated reactions 
Infusion associated reactions, commonly observed with monoclonal antibodies, include AEs with 
onset date typically within 24 hours from the start of each isatuximab infusion (See Section 6.6 of 
the protocol for guidelines for IARs management). As described above, IARs are considered to be 
AESI. 
Two analyses of IARs will be performed. The first one will be based on the investigator’s 
reporting of IARs (i.e., as AESIs). For each IAR-AESI, the sites were instructed to report a generic 
term (infusion related reaction) and each individual symptom. For IAR analyses based on the 
generic term, a customized MedDRA query (CMQ) including the single preferred term of infusion 
related reaction will be used. 
The second analysis of IAR will include TEAEs occurring within 24 hours (one table including 
causally related TEAEs, one table including all TEAEs regardless of causal relationship) from the 
start of each isatuximab infusion (i.e., TEAEs with onset on the same calendar day of the 
isatuximab infusion or on the following day). 
Respiratory AEs 
Analysis of respiratory TEAEs will focus particularly on the groupings by CMQ. 
Hematological analyses 
Neutropenic complications will focus particular on the groupings by CMQ. 
2.1.4.2 Deaths 
The deaths observation period are based on the observation periods defined in Section 2.1.4.  
• 
Death on-treatment:  deaths occurring during the on-treatment 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, clinical chemistry, and 
urinalysis. 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 flow charts and as 
clinically indicated. The laboratory parameters will be classified as follows:   
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• 
Hematology  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, mean 
corpuscular volume, red blood cell count, platelet count, prothrombin time (expressed 
as international normalized ratio), activated partial thromboplastin time 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• 
Clinical chemistry  
- 
Metabolism: glucose, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium, corrected serum calcium, 
phosphate, magnesium  
- 
Renal function: creatinine, blood urea nitrogen, uric acid, e-GFR (revised equations 
for e-GFR in Japanese) 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total and conjugated (direct) bilirubin 
- 
Pregnancy test: serum β-human chorionic gonadotropin (all female patients)  
- 
Hepatitis screen: hepatitis B surface antigen (HBs-Ag, HBc-Ab, and HBs-Ab), HBV-
DNA, anti-hepatitis-C antibody (HCV-Ab) 
Urine samples will be collected as follows:  
- 
Urinalysis – quantitative: pH, leukocytes, erythrocytes and specific gravity 
- 
Urinalysis – qualitative: blood, ketones, bilirubin, leucocytes, nitrites, proteins and 
glucose 
2.1.4.4 Vital signs variables 
Vital signs include: heart rate, respiratory rate, temperature, body weight, and systolic/diastolic 
blood pressure. 
2.1.4.5 Electrocardiogram variables 
Electrocardiogram variable include: 12 leads electrocardiogram and 2-D echocardiogram or 
MUGA scan. 
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2.1.4.6 Other safety endpoints 
Other safety endpoints include: 
• 
Cytokines 
- 
TNF-α,IL-4, IL-6, IL-1-β, IFN-γ 
• 
IAR laboratory test 
- 
Complement (C3a, C4, CH50) 
- 
Serum tryptase 
• 
Chest X-ray at baseline and as clinically indicated 
• 
Tumor lysis syndrome (TLS) 
2.1.5 Pharmacokinetic variables  
The PK sampling times were provided in the study flowcharts. 
Isatuximab concentrations will be analyzed with the PKDMS software (Pharsight) using non-
compartmental methods for all cohorts. The following PK parameters will be calculated following 
the first administration: 
• 
Concentration observed at the end of an IV infusion (Ceoi ) 
• 
Maximum observed concentration (Cmax ) 
• 
Time to reach Cmax (tmax ) 
• 
Concentrations just before drug infusion (Ctrough ) 
• 
AUC over the dosing interval (AUC1week ) 
Ctrough are defined as sample collected before dosing of all cycles, and in a time window of 6 to 8 
days after the previous start of infusion for the QW administration. 
2.1.6 CD38 Receptor density 
CD38 RD will be assessed from bone marrow aspirates at baseline. 
2.1.7 Immune response 
Human ADA status to isatuximab was assessed during the study as defined in the protocol. 
Observation period 
The observation period will be divided into 2 periods: ADA pre-treatment and ADA on-study 
observation. 
• 
ADA pre-treatment period: The ADA pre-treatment period is defined as the time from 
signed informed consent to the first isatuximab administration. 
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• 
ADA on-study observation period: the ADA on-study observation period is defined as the 
time from first isatuximab administration until Cycle 10. 
Patients with at least one ADA result during the ADA on-study observation period will be 
considered evaluable for ADA. 
ADA attributes: 
• 
Pre-existing ADA is defined as ADA that was present in samples drawn during the ADA 
pretreatment period. 
• 
Treatment boosted ADA is defined as preexisting ADA with an increase in titer value 
between pre-treatment and post-treatment samples of at least two titer steps during the 
ADA on-study observation period. With a 2-fold serial dilution, this means that the 
posttreatment sample titer value is at least (≥) 4 fold of pretreatment titer value. 
• 
Treatment-induced ADA is 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. 
• 
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 ADA 
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 patient’s last sampling time point is ADA negative. 
• 
A 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 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between), OR 
• 
Indeterminate ADA response is defined by:  
- 
Treatment induced ADA detected only at the last sampling time point with all previous 
samples being negative, OR 
- 
The last two samples being ADA-positive and separated by a period of less than 16 
weeks. 
ADA response endpoints: 
- 
An ADA positive patient is defined as a patient with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time during the on-study observation 
period 
- 
ADA incidence is defined as the number of ADA positive patients among evaluable 
patients divided by the number of evaluable patients. 
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- 
ADA prevalence is defined as the sum of the number of patients with preexisting 
ADA and the number of patients with treatment induced ADAs, divided by the number 
of evaluable patients 
2.1.8 Pharmacodynamic/genomics endpoints  
Not applicable. 
2.1.9 Quality-of-life endpoints  
Not applicable. 
2.1.10 Health economic endpoints  
Not applicable. 
2.1.11 Exploratory endpoints 
Exploratory endpoints are FISH, MRD, immune genetic determinants, immune phenotyping bone 
marrow/blood, and soluble CD38. 
2.1.12 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies after discontinuation of IMP will be assessed. 
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 informed consent. A listing of 
screening failure patients (screened patients who were not treated with isatuximab) and reason for 
screening failure will be provided. 
The number and percentage (when applicable) of patients in each of the following analysis 
population will be provided: 
• 
All treated/safety population 
• 
DLT evaluable population 
• 
Pharmacokinetics population 
• 
ADA evaluable population 
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For all above categories (except for the all treated population) percentages will be calculated using 
the number of patients in the all treated population. For the all treated population, no percentages 
will be calculated. 
For patient study status, the number and percentage of patients in each of the following categories 
will be provided using the all treated/safety population: 
• 
Patients off treatment and reasons for treatment discontinuation 
• 
Patients on treatment at time of the analysis cut-off date 
Major deviation potentially impacting efficacy/safety analyses include: 
• 
No prior treatment with IMiD and PI (for 2 cycles or 2 months of treatment) 
• 
Was not refractory to the most recently received both IMiD and PI included therapy 
• 
Did not achieve an MR or better to all prior lines of therapy. 
All critical or major deviations will be summarized in a table giving numbers and percentages of 
patients with deviations. Protocol deviation will also be listed. 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable, as this is a non-randomized study. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 All treated/safety populations 
The all treated/safety population will include all patients who have given their informed consent 
and who have received at least one dose (even incomplete) of isatuximab. 
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the treatment actually received. 
2.3.2 DLT evaluable population 
The DLT evaluable population is the subset of patients from the all treated population who have 
completed the first cycle which consists of 4 administrations of the IMP, or they discontinued the 
IMP before completion of the first cycle for a DLT. In practice, a “Dose-Limiting Toxicities” form 
should have been filled in at the end of Cycle 1. If there are missing or incomplete data that 
influence the evaluation of DLT the patient will not be evaluable for DLT. Patients excluded from 
this population will be replaced. 
2.3.3 Pharmacokinetic population  
The PK parameter analysis will be performed on the all treated/safety population who have a 
concentration data. 
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2.3.4 ADA population 
The ADA evaluable population will include all treated patients with at least one ADA assessment 
with a reportable during the ADA on-study observation periods. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of available data, mean, standard deviation, 
median, minimum, and maximum for each treatment group. Categorical and ordinal data will be 
summarized using the number and percentage of patients in each dose level cohort. 
Parameters described in Section 2.1.1 will be summarized by dose level cohort and overall group 
using descriptive statistics.  
Past medical or surgical history other than multiple myeloma will be summarized by SOC (sorted 
by internationally agreed order) and PT (sorted by descending frequency in overall group and 
alphabetical order) for the all treated population. 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
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 anatomical therapeutic chemical (ATC) class (anatomical 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 (anatomical or therapeutic) 
linked to the medication. Therefore, patients may be counted several times for the same 
medication. 
The table for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on the overall incidence across all dose levels (i.e., 
the all patients column). In case of equal frequency regarding ATCs, alphabetical order will be 
used. 
Pre-medications 
Number (%) of patients with pre-medications (antihistamine, corticosteroids, h2 blocker, and 
acetaminophen) will be summarized by each administration until 7 and more than 7. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure will be assessed and summarized by dose level cohort within the all 
treated population (Section 2.3.1). 
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The dose information will be assessed by the following variables. 
• 
Number of cycles started 
• 
Duration of isatuximab exposure (or time on-treatment) in weeks: defined as {min(date of 
last dose of isatuximab + X days, date of death) – first dose date} / 7 (X equals to 7 in 
cycle 1 and 14 in the subsequent cycle). The theoretical duration of a cycle is 28 days 
• 
Actual dose in mg/kg: for a given cycle and day of administration, the actual dose in mg/kg 
corresponds to the actual dose in mg administered at this time point divided by the actual 
body weight as measured at each time point 
• 
Cumulative dose in mg/kg: the cumulative dose is the sum of all actual doses of 
isatuximab, expressed in mg/kg, given from first to last administration 
• 
Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) 
divided the duration of isatuximab exposure (in weeks) 
• 
Relative dose intensity (RDI) in %: 100 × ADI (mg/kg/week) / Planned Dose Intensity 
(mg/kg/week) 
Planned dose intensities corresponds to the planned dose (mg/kg) received at Day 1 of cycle 1, 
multiplied by the theoretical total number of doses during the started cycles (count 2 for Q2W and 
4 for QW), divided by the theoretical cycle duration expressed in weeks (i.e., 4 weeks), regardless 
of dose/schedule changes (as defined in the protocol section 6.5). ADI and RDI will be calculated 
separately in cycle 1 and subsequent cycles respectively, due to the difference of administration 
interval. 
Total number of cycles started, number of cycles started by patients as a quantitative variable and 
by category (i.e., number [%] of patients receiving at least 1 cycle, at least 2 cycles…), duration of 
isatuximab exposure, cumulative dose, ADI, RDI, and RDI by category (< 80%, [80 - 105%), 
≥105%) will be summarized by descriptive statistics. 
The following variables will be computed to describe dose delays and interruption: 
• 
Cycle delayed is defined as follows: 
- 
A cycle is deemed as delayed if the start date of the current cycle - 28 - start date of the 
previous cycle is >3 days. Cycle delay is not defined for the first cycle. 
• 
Infusion delay: within cycle 1, an infusion is deemed to be delayed if start date of the 
current administration – start date of previous administration – the theoretical duration 
(which is 7 days) is ≥3 days. For subsequent cycles (≥cycle 2), an infusion is deemed to be 
delayed if start date of the current administration – start date of previous administration – 
the theoretical duration (which is 14 days) is ≥4 days 
• 
Dose interruption: A dose will be considered to be interrupted if the isatuximab 
administration is temporarily stopped during an infusion and then restarted (typically in 
case of Grade 2 IARs). 
• 
Dose reduction: although not allowed in the study protocol, potential dose reductions will 
be screened and reported in the clinical study report. The first administration will not be 
counted as a dose reduction. For the second and subsequent isatuximab administrations, 
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Statistical Analysis Plan  
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Page 24 
dose reduction will be determined using the dose level intervals provided in Table 5, by 
comparing the current dose level to the previous dose level. If the current dose level is not 
within the same dose level interval as the previous dose level, then the current dose level is 
considered reduced. 
Table 5 – Dose reduction criteria 
Actual dose level 
Dose level interval 
Dose level 1 (10 mg/kg) 
>0 mg/kg and ≤15 mg/kg 
Dose level 2 (20 mg/kg) 
>15 mg/kg and ≤25 mg/kg 
 
• 
Infusion not completed: patients who received less than 90% of the planned dose at an 
infusion. 
Dose modification will be analyzed at the patient, cycle, and total number of isatuximab 
administration levels as follows: 
• 
Patient level 
- 
Number of patients 
- 
Number (%) of patients with at least 1 dose reduction 
- 
Number (%) of patients with at least 1 infusion interrupted 
- 
Number (%) of patients with at least 2 infusion interrupted 
- 
Number of patients who could have a cycle delayed (patients who received ≥2 cycles, 
used for % calculation in this section): 
- 
Number (%) of patients with at least 1 cycle delayed 
- 
Number (%) of patients with a maximum cycle delayed between 4 and 7 days 
- 
Number (%) of patients with a maximum cycle delayed > 7 days 
- 
Number of patients who could have an infusion delay (patients who received ≥2 
infusions, used for % calculation in this section). 
- 
Number (%) of patients with at least 1 infusion delay. 
• 
Cycle level 
- 
Number of cycles administered (used for % calculation for this level) 
- 
Number (%) of cycles delayed 
- 
Number (%) of cycles with delay between 4 and 7 days 
- 
Number (%) of cycles with delay on > 7 days 
• 
Total number of isatuximab administration level 
- 
Total number of isatuximab administration (used for % calculation for this level) 
- 
Number (%) of isatuximab administration interrupted 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Page 25 
- 
Number (%) of isatuximab infusions interrupted more than once 
- 
Number of infusion interrupted at (with % calculated using the total number of 
infusions interrupted): 1st infusion, 2nd infusion, subsequent infusions. 
- 
Time from infusion start to first interruption in minutes (quantitative (descriptive 
statistics) and qualitative: 5<, 5-10, 11-30, 31-40, 41-50, 51-60, 61-90, 91-120, 
>120), missing. 
- 
Number (%) of infusions not completed (patients who received less than 90% of the 
planned dose) 
Duration of infusion is defined as the time from the start (date/time) of infusion to the end 
(date/time) of infusion. It will be summarized with descriptive statistics for first and subsequent 
infusions. A listing of dosing data will be provided and include the following variables, number of 
cycles started, cycle-day, start date, cycle delayed, actual dose in mg/kg, dose interruption, dose 
reduced and dose not complete. 
2.4.4 Analyses of efficacy endpoints 
BOR will be summarized. 
A listing of best percent change in % plasma cell in bone marrow biopsy will be provided and will 
include the following variables: measurable paraprotein at baseline, best percent change in 
paraprotein, BOR, baseline plasma cells count, best post baseline percent change in plasma cells 
count (only for CR confirmation) and MRD. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by dose level cohort.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.1. Unless 
otherwise specified, the baseline value is defined as the last available value before the first 
isatuximab administration. 
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.  
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Statistical Analysis Plan  
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Page 26 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
the adverse event will be classified as pre-treatment, treatment-emergent, or post-treatment, 
according to the cycle number or visit of onset. The algorithm for imputing date of onset will be 
conservative and will classify an AE as treatment emergent unless there is definitive information 
to determine it is pretreatment or post-treatment. Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5. 
The grade will be taken into account in the summary. For patients with multiple occurrences of the 
same event during the observation period, the maximum grade is used. 
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 and decreasing frequency of PTs within SOCs in the highest 
dose level cohort will define the presentation order for all other tables unless otherwise specified. 
The following treatment-emergent adverse event summaries will be generated by dose level for 
the safety population. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any  
- 
Treatment-emergent adverse event (TEAE) 
- 
Grade 3-5 TEAE 
- 
Drug-related TEAE 
- 
Grade 3-5 drug-related TEAE 
- 
Serious TEAE 
- 
Drug-related serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
Dose limiting toxicity 
- 
Infusion associated reaction (excluding symptoms) 
- 
Grade 3-5 infusion associated reaction (excluding symptoms) 
• 
All TEAEs by primary SOC, HLGT, HLT and PT, showing number (%) of patients with at 
least 1 treatment-emergent adverse event sorted by the SOC internationally agreed order. 
The other levels (HLGT, HLT and PT) will be presented in alphabetical order. 
• 
All TEAEs by grade, primary SOC, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent adverse event by grade (i.e., all grade, ≥ grade 3). 
• 
All serious TEAEs by primary SOC and PT, showing the number (%) of patients with at 
least 1 serious treatment-emergent adverse event. 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 27 
• 
All TEAEs related to isatuximab, by primary SOC and PT, showing the number (%) of 
patients with at least 1 treatment-emergent adverse event related to isatuximab. 
• 
All serious TEAEs related to isatuximab, by primary SOC and PT, showing the number 
(%) of patients with at least 1 treatment-emergent serious adverse event related to 
isatuximab. 
• 
All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing the 
number (%) of patients. 
• 
All TEAEs leading to dose delay or interrupted, by primary SOC and PT, showing the 
number (%) of patients. 
• 
All TEAEs with a fatal outcome, by primary SOC and PT, showing the number (%) of 
patients. 
• 
All treatment-emergent DLT by primary SOC and PT, showing the number (%) of patients. 
• 
All treatment-emergent IAR by primary SOC and PT, showing the number (%) of patients. 
• 
IAR-AESI (using the CMQ corresponding to the generic term of infusion related reaction 
reported by investigator as an AESI): 
- 
Analysis by patient: number of patients (used as denominator), worst grade by patient, 
number of episodes by patient (only 1 episode, ≥1 episode, ≥2 episodes, …. – an 
episode corresponds to a unique AE reference ID), first occurrence of IARs, patients 
with IAR at the first and/or subsequent isatuximab infusion, and number (%) of 
patients with at least 2 episodes of IARs at the same infusion 
- 
Analysis by infusion: number of infusions (used as denominator), worst grade by 
infusion (a patient can have several IAR episodes at the same infusion). 
- 
Analysis by episode: number of episode (used as denominator), proportion of IARs 
occurring at each infusion, IAR duration, and day of onset 
• 
IAR-AESI including symptoms as reported by investigator 
- 
Summary of IAR-AESI by SOC and PT 
- 
Listing of IAR-AESI 
All AEs, AEs related to isatuximab, DLTs, IARs, respiratory AE, neutropenic complications, 
SAEs, and AEs leading to permanent treatment discontinuation are listed separately. 
2.4.5.2 Deaths 
Number (%) of patients who died by study period (on-treatment and post-treatment) and within 60 
days from first dose of study treatment, and cause of death will be summarized. All deaths with 
relevant information (which are study period, cause of death, death date, etc.) will be listed. 
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Statistical Analysis Plan  
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Version number: 2 
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Page 28 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory tests will be calculated for each planned visit (for cycle 1 to cycle 3) 
by dose level cohort. 
Each laboratory test result will be graded by NCI CTCAE (version 4.03), when applicable. 
Sponsor generic ranges are used for the grading of laboratory results, otherwise site ranges are 
used. For patients with multiple occurrences of the same laboratory variable during the on-
treatment period, the maximum grade (worst) per patient will be used. The number (%) of patients 
with abnormal laboratory tests at baseline and during the on-treatment period will be presented by 
all grades and each grade. At baseline, the last available value before or on the date of first study 
treatment administration (excluding repeated tests) will be used. 
All laboratory variables will be listed. 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables will be calculated for each planned visit (pre-infusion, mid-
infusion and end-infusion for cycle 1 to cycle 3) by dose level cohort. 
The incidence of potentially clinically significant abnormalities (PCSAs) at any time during the 
on-treatment period will be summarized by dose level cohort. 
The PCSA values are defined as abnormal values considered medically important by the Sponsor 
according to predefined criteria/thresholds based on literature review and defined by the Sponsor 
for vital signs. 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 (Appendix A). 
A listing of vital signs will be provided. 
2.4.5.5 Analyses of electrocardiogram variables 
Results of ECG will be listed. 
2.4.5.6 Analyses of other safety endpoints 
ECOG PS and results of chest X-ray will be listed. 
The patients with TLS reported under the TLS standard MedDRA query (SMQ) will be listed. 
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Statistical Analysis Plan  
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Page 29 
2.4.6 Analyses of pharmacokinetic, CD38 receptor density and immune response 
2.4.6.1 Pharmacokinetic variables 
All individual concentrations and all pharmacokinetic parameters if isatuximab will be tabulated 
using descriptive statistics: arithmetic and geometric mean, median, standard deviation, standard 
error of the mean (SEM) (optional), coefficient of variation (CV), minimum, maximum and 
number of available observations, using PKDMS. 
Individual and mean plasma concentration over time (Day) and individual and mean PK 
parameters will be represented graphically after 1st administration by dose level cohort. 
Individual and mean Ctrough of isatuximab will be represented graphically as function of actual 
sampling time (Day) over study period by dose level cohort. 
2.4.6.2 CD38 receptor density 
CD38 RD will be summarized with descriptive statistics by dose level cohort and listed with BOR. 
2.4.6.3 Immune response 
Using the ADA evaluable population, the number (%) of patients will be provided for the 
following if at least one positive observed: 
• 
Pre-existing ADA 
• 
ADA negative at baseline 
• 
On study ADA 
- 
Treatment-induced ADA 
- 
Persistent ADA 
- 
Transient ADA 
- 
Treatment boosted ADA 
- 
Indeterminate ADA 
- 
Last sample positive 
• 
ADA prevalence 
• 
ADA incidence 
Data listing of each ADA sample results for patients evaluable for ADA will be listed. 
2.4.7 Analyses of quality of life/health economics variables 
Not applicable. 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 30 
2.4.8 Analyses of exploratory variables 
CD38 RD and soluble CD38 will be summarized with descriptive statistics for responder/non-
responder. A responder is a patient with IAC assessment response ≥ PR. In addition, summary of 
BOR will be provided by CD38 RD level and immune generic determinants, and a graph showing 
responder/non-responder rate (in y-axis) by CD38 RD level, soluble CD38 and immune 
phenotyping will be provided. All variables are listed. 
2.4.9 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapy for MM will be listed and not summary table will be provided. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
For the data censored at detection limits, its value will be substituted by DL/2.  
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  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. 
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Statistical Analysis Plan  
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Page 31 
For post anticancer treatments, if the anticancer treatment start date is missing, it will be imputed 
as follows: 
1. If the anticancer treatment start day is missing and the anticancer treatment start month and 
year are the same as the study treatment end month and year, the anticancer treatment start 
day will be set equal to the date of last study treatment administration + 1. 
2. If the anticancer treatment start day is missing and the anticancer treatment start month is 
not missing and the anticancer treatment start year is after the study treatment end year, the 
anticancer treatment start day will be set to 01. 
3. If the anticancer treatment start day is missing and the anticancer treatment start month is 
after the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01. 
4. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is the same as study treatment end year, the anticancer treatment start date will be 
set equal to the date of last study treatment administration + 1. 
5. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is after the study treatment end year, the anticancer treatment start day and month 
will each be set to 01. 
6. If the anticancer treatment start day is missing and anticancer treatment start month is 
before the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01. 
7. If the anticancer treatment start day, start month and start year is missing, the anticancer 
treatment start date will be set equal to the treatment end date + 1. 
Handling of adverse events with missing/partial dates 
Missing or partial adverse event onset dates and times will be imputed so that if the partial adverse 
event onset date/time information or cycle/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. No imputation of adverse event end dates/times will be 
performed. These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of adverse event resolution. 
Handing of adverse events with missing grade 
Missing grades, if any, will be included in the “all grade” category. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to isatuximab is missing, then the relationship to isatuximab 
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. 
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Statistical Analysis Plan  
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Page 32 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points 
An episode occurred during a cycle if the date of sampling is equal to or after (≥) the first date of 
the cycle, but prior to the first day of the next cycle. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data and vital signs will be used for only 
computation of worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses 
Data from all sites will be pooled together for analysis. 
2.5.7 Statistical technical issues 
Not applicable. 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 33 
3 
INTERIM ANALYSIS 
Not applicable. 
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Statistical Analysis Plan  
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 34 
4 
DATABASE LOCK 
The database lock is planned to be locked twice after phase 2. The first is at approximately 4 
months after last patient first dosed. The second is at approximately 12 months after last patient 
first dosed. 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 35 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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Statistical Analysis Plan  
30-Aug-2018 
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 36 
6 
REFERENCES 
Not applicable. 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 37 
7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Sponsor generic ranges 
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Statistical Analysis Plan  
30-Aug-2018 
SAR650984-TED14095 (Phase 1) - isatuximab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 38 
Appendix A 
Potentially clinically significant abnormalities criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
 
Parameter 
PCSA 
Comments 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
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Statistical Analysis Plan  
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Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 39 
Appendix B 
Sponsor generic ranges 
Table 6 – Hematological parameters 
LBTESTCD 
LBTEST 
GENDER
LBSTRESU 
LBGNNRLO 
HGB 
Hemoglobin 
F 
g/L 
120 
HGB 
Hemoglobin 
M 
g/L 
135 
LYM 
Lymphocytes 
 
10^9/L 
1 
NEUT 
Neutrophils 
 
10^9/L 
1,8 
PLAT 
Platelets 
 
10^9/L 
150 
WBC 
Leukocytes 
 
10^9/L 
4,5 
EOS 
Eosinophils 
 
10^9/L 
0 
BASO 
Basophils 
 
10^9/L 
0 
MONO 
Monocytes 
 
10^9/L 
0,18 
HCT 
Hematocrit 
M 
% 
0,41 
HCT 
Hematocrit 
F 
% 
0,36 
RBC 
Erythrocytes 
F 
10^12/L 
4 
RBC 
Erythrocytes 
M 
10^12/L 
4,5 
 
Table 7 – Biochemistry parameters 
LBTEST 
LBSTRESU 
LBGNNRLO - LBGNNRHI 
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
NA-17 
Calcium 
mmol/L 
2,2 - 2,6 
Chloride 
mmol/L 
80 - 115 
Glucose 
mmol/L 
3,9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Potassium 
mmol/L 
3,5 - 5 
Magnesium 
mmol/L 
0,8 - 1,2 
Sodium 
mmol/L 
129 - 160 
Phosphate 
mmol/L 
1 - 1,4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3,6 - 7,1 
 
(electronic 
 
 
 
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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 I/ II Study of Isatuximab (Anti-CD38 mAb) administered as a single agent 
in Japanese Patients With Relapsed AND Refractory Multiple Myeloma  
SAR650984-TED14095 (Phase 2) 
STATISTICIAN: 
 
DATE OF ISSUE: 14-FEB-2018 
 
 
Total number of pages: 
40 
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Statistical Analysis Plan  
14-FEB-2018 
SAR650984-TED14095 (Phase 2) - isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
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 AND RANDOMIZATION ......................................................................................6 
1.2 
OBJECTIVES...................................................................................................................................6 
1.2.1 
Primary objectives............................................................................................................................6 
1.2.2 
Secondary objectives.......................................................................................................................6 
1.2.3 
Exploratory objectives......................................................................................................................6 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................7 
1.4 
STUDY PLAN...................................................................................................................................7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................8 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .......................8 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ......................................................................9 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................9 
2.1.1 
Demographic and baseline characteristics ......................................................................................9 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) .............................................11 
2.1.3 
Efficacy endpoints..........................................................................................................................12 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................12 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................13 
2.1.4 
Safety endpoints ............................................................................................................................14 
2.1.4.1 
Adverse events variables...............................................................................................................14 
2.1.4.2 
Deaths............................................................................................................................................16 
2.1.4.3 
Laboratory safety variables............................................................................................................16 
2.1.4.4 
Vital signs variables .......................................................................................................................17 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................17 
2.1.4.6 
Other safety endpoints...................................................................................................................17 
2.1.5 
Pharmacokinetic variables .............................................................................................................17 
2.1.6 
Immunogenicity..............................................................................................................................17 
2.1.7 
Biomarker endpoints ......................................................................................................................19 
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2.1.7.1 
Receptor density ............................................................................................................................19 
2.1.7.2 
Immune genetic determinants........................................................................................................19 
2.1.7.3 
Immune phenotyping......................................................................................................................19 
2.1.7.4 
Soluble CD38.................................................................................................................................19 
2.1.8 
Quality-of-life endpoints .................................................................................................................19 
2.1.9 
Health economic endpoints............................................................................................................19 
2.1.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................19 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................19 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................20 
2.3 
ANALYSIS POPULATIONS...........................................................................................................20 
2.3.1 
All treated/safety population...........................................................................................................20 
2.3.2 
Pharmacokinetic population...........................................................................................................21 
2.3.3 
ADA evaluable population..............................................................................................................21 
2.4 
STATISTICAL METHODS .............................................................................................................21 
2.4.1 
Demographics and baseline characteristics ..................................................................................21 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) .............................................21 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................22 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................24 
2.4.4.1 
Analysis of primary efficacy endpoint.............................................................................................24 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................24 
2.4.4.3 
Multiplicity issues ...........................................................................................................................25 
2.4.4.4 
Additional efficacy analysis(es)......................................................................................................25 
2.4.5 
Analyses of safety data..................................................................................................................25 
2.4.5.1 
Analyses of adverse events ...........................................................................................................25 
2.4.5.2 
Deaths............................................................................................................................................28 
2.4.5.3 
Analyses of laboratory variables....................................................................................................28 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................29 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................29 
2.4.5.6 
Analyses of other safety endpoints................................................................................................29 
2.4.6 
Analyses of pharmacokinetic .........................................................................................................29 
2.4.6.1 
Pharmacokinetic variables .............................................................................................................29 
2.4.7 
Immune response ..........................................................................................................................30 
2.4.8 
Analyses of Biomarker variables....................................................................................................31 
2.4.8.1 
Receptor density ............................................................................................................................31 
2.4.8.2 
Genetic variables ...........................................................................................................................31 
2.4.8.3 
Other variables...............................................................................................................................31 
2.4.9 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................31 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................31 
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2.5.1 
General conventions ......................................................................................................................31 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................32 
2.5.3 
Missing data...................................................................................................................................32 
2.5.4 
Windows for time points.................................................................................................................34 
2.5.5 
Unscheduled visits .........................................................................................................................34 
2.5.6 
Pooling of centers for statistical analyses......................................................................................34 
2.5.7 
Statistical technical issues .............................................................................................................34 
3 
INTERIM ANALYSIS .....................................................................................................................35 
4 
DATABASE LOCK........................................................................................................................36 
5 
SOFTWARE DOCUMENTATION .................................................................................................37 
6 
REFERENCES...............................................................................................................................38 
7 
LIST OF APPENDICES.................................................................................................................39 
APPENDIX A SPONSOR GENERIC RANGES .........................................................................................40 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibodies 
AESI: 
adverse events of special interest 
CT: 
computed tomography 
DFU: 
duration of follow-up 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
e-CRF: 
electronic case report form 
FISH: 
fluorescence in situ hybridization 
FLC: 
free light chain 
IAC: 
independent adjudication committee 
IAR: 
infusion associated reaction 
IFN-γ: 
interferon-gamma 
IL: 
interleukin 
IV: 
intravenous 
MM: 
multiple myeloma 
MRD: 
minimal residual disease 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
MUGA: 
multigated acquisition 
NCI-CTCAE: 
National Cancer Institute Common Toxicity Criteria for Adverse Event 
ORR: 
overall response rate 
OS: 
overall survival 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PS: 
Performance Status 
RD: 
receptor density 
RRMM: 
relapsed and refractory multiple myeloma 
SAP: 
statistical analysis plan 
TNF-α: 
tumor necrosis factor alpha 
 
 
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Statistical Analysis Plan  
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
This is an open-label, single arm, local, multi-center study conducted in 2 parts, phase 1 and phase 
2. This statistical analysis plan (SAP) describes the statistical methods to be used for the analyses 
of data collected during the phase 2 part of the study. For the phase 1 part, the SAP is described 
separately. This SAP should be read in conjunction with the study protocol and electronic case 
report form (e-CRF). 
1.1 
STUDY DESIGN AND RANDOMIZATION 
The phase 2 part of TED14095 is a study of isatuximab administered as a single agent as an 
intravenous (IV) infusion every week (QW) during cycle 1 followed by every 2 weeks (Q2W) 
during subsequent cycles to adult patients with relapsed and refractory multiple myeloma (MM). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of the phase 2 part of this study is to evaluate efficacy of isatuximab at the 
recommended dose determined in phase 1 part as assessed by overall response rate (ORR) in 
Japanese patients with relapsed and refractory multiple myeloma (RRMM). 
1.2.2 Secondary objectives 
Secondary objectives of the phase 2 part of the study are: 
• To evaluate the safety including immunogenicity of isatuximab. The severity, frequency 
and incidence of all adverse events will be assessed. 
• To evaluate the pharmacokinetic (PK) profile of isatuximab in the proposed dosing 
schedule. 
• To assess the relationship between baseline CD38 receptor density (RD) on MM cells and 
efficacy. 
1.2.3 Exploratory objectives 
The following exploratory objectives will be investigated in the end of phase 2 part of the study. 
• To assess minimal residual disease (MRD) in patients achieving CR and correlate with 
clinical outcome. 
• To investigate the relationship of soluble CD38 and parameters of PK and clinical 
response. 
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• To investigate the relationship between multiple myeloma molecular subtype (as defined 
by cytogenetics/ fluorescence in situ hybridization (FISH)) and parameters of clinical 
response. 
• To investigate the relationship between immune genetic determinants, immune phenotype 
and parameters of clinical response. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The phase 2 part of the study aims to evaluate 33-36 subjects which include the subjects in Phase 
1 part at the dose level determined as MTD/recommended dose. Given an assumed true ORR of 
28%, the null hypothesis ORR ≤ 10% will be rejected using an exact binomial test at a one-sided 
alpha of 0.025 with at least 80% power, if the observed ORR is greater than or equal to 24.2% 
(i.e., 8 responders). The sample size calculation was performed using SAS ver. 9.4 SAS/STAT 
13.2, power procedure. 
1.4 
STUDY PLAN 
Safety evaluations are performed continuously throughout the study and included the following: 
• AEs according to the National Cancer Institute Common Toxicity Criteria for Adverse 
Event (NCI-CTCAE) v. 4.03 grading scale 
• Vital signs 
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
• 12 lead electrocardiogram (ECG) or 2-D echocardiogram or Multigated Acquisition 
(MUGA) scan 
• Chest X-ray 
• Laboratory tests in blood and urine 
• Level of human anti-drug antibodies (ADA) 
• Cytokines (tumor necrosis factor alpha [TNF-α], interleukin [IL]-1-β, IL-4, IL-6, 
interferon-gamma [IFN-γ]), complement activators and tryptase 
Disease response evaluations are performed every 4 weeks, unless otherwise stated, including: 
• M-protein quantification (serum and/or 24-hour urine, protein electrophoresis and 
immunoelectrophoresis), serum free light chain (FLC) levels 
• Serum β2-microglobulin, quantitative immunoglobulins and serum calcium 
• Bone skeletal survey, computed tomography (CT) scan or magnetic resonance imaging 
(MRI) as clinically indicated 
• Radiologic imaging (CT/MRI scan) of plasmacytoma 
• Survival status 
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The following additional evaluation is also performed: 
• CD38 RD on bone marrow samples 
PK samples are collected in all patients receiving isatuximab as depicted in the PK study 
flowcharts included in the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). The protocol history table below 
gives the timing, rationale, and key details of major changes to the protocol statistical section. 
Table 1 – Protocol amendment statistical changes 
Amendment 
Number 
Date Approved 
Rationale 
Description of statistical changes 
1 
13-May-2016 
To harmonize the other global 
studies 
Summary of prior anti-cancer therapy 
1 
13-May-2016 
To harmonize the other global 
studies 
Overview of TEAEs 
1 
13-May-2016 
To harmonize the other global 
studies 
Deletion of the description in “Analyses of 
Pharmacokinetic variables” 
 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable as this is the 1st version of the 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 available value before the first isatuximab administration, 
unless otherwise specified. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are gender (Male, Female), ethnicity (Hispanic or Latino , Not Hispanic or 
Latino, Not reported, and Unknown), race (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or Other Pacific Islander, White, Not reported, Unknown), 
age in years (quantitative and qualitative variable : < 65, [65 - 75)  and ≥ 75 years), weight (kg), 
and ECOG PS at baseline. 
Medical or surgical history 
Medical or surgical history other than MM will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version in effect at Sanofi (or the data management vender) at 
the time of the data base lock. 
Disease characteristics at initial diagnosis 
The following MM characteristics at initial diagnosis will be described: time from initial 
diagnosis to first isatuximab administration (in years) and by category (<5 years and ≥ 5 years), 
International Staging System (ISS) stage, and MM subtype (as collected in the e-CRF). 
Disease characteristics at study entry 
The following MM characteristics at study entry will be displayed: derived ISS stage (Table 2), 
measurable paraprotein at baseline (Table 3), percent of plasma cells in bone marrow (quantitative 
results and by category: 0, (0 - 5%), [5 - 20%), [20 - 50%) and ≥ 50%), patients with 
plasmacytomas, patients with bone lesions, serum β2-microglobulin level in mg/L (quantitative 
results and by category: < 3.5 mg/L, [3.5 - 5.5 mg/L) and ≥ 5.5 mg/L), serum albumin in g/L 
(quantitative results and by category: < 35 g/L and ≥ 35 g/L). 
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Table 2 – ISS staging definition 
Stage 
Definition 
Stage I 
Serum β2-microglobulin <3.5 mg/L and serum albumin ≥ 35 g/L 
Stage II 
serum β2-microglobulin <3.5 mg/L and serum albumin <35 g/L  
or 
 serum β2-microglobulin 3.5 - <5.5 mg/L regardless of serum albumin levels 
Stage III 
Serum β2-microglobulin ≥5.5 mg/L regardless of serum albumin levels 
 
Table 3 – Derivation of measurable paraprotein at study entry 
Measurable paraprotein 
Criteria 
Serum M-Protein 
Serum M-protein ≥ 0.5 g/dL  
and  
urine M-Protein < 200 mg/24hours or missing 
Urine M-Protein 
Serum M-protein < 0.5 g/dL or missing 
and 
urine M-protein ≥ 200 mg/24hours 
Serum M-Protein and Urine M-Protein 
Serum M-protein ≥ 0.5 g/dL 
and 
urine M-protein ≥ 200 mg/24 hours 
 
 
Molecular subtype at initial diagnosis 
Molecular subtype included cytogenetics analysis by FISH (as collected in the e-CRF). 
Molecular subtype at study entry 
Molecular subtype included cytogenetics analysis by FISH which are 17p deletion, t (4, 14), and t 
(14; 16). High risk group is defined as patients with at least one chromosomal abnormality. 
Considering many missing is observed, two kinds of summaries will be provided with imputation 
from results at initial diagnosis and no imputation (used results at study entry only). 
Prior anticancer therapies 
• Prior anticancer treatments: number of prior lines (2, 3, 4, 5, 6, 7 and ≥ 8 and as a 
quantitative variable), main category of drug (i.e., alkylating agent, anthracycline, 
proteasome inhibitor, immunomodulatory drugs and others), drug name (i.e., melphalan, 
cyclophosphamide, doxorubicin, lenalidomide, pomalidomide, thalidomide, bortezomib, 
carfilzomib, ixazomib, elotuzumab, and panobinostat), time from completion of last line of 
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treatment to first Investigational Medicinal Product (IMP) administration (months), best 
response to last line, duration of last line of therapy. 
In addition, the refractory status to each anticancer treatment will be derived. A patient is 
considered to be refractory if any of the following conditions are met: 
- 
Progression date and anticancer treatment end date are complete and progression date 
is within (≤) 60 days of anticancer treatment end date (progression date – anticancer 
treatment end date ≤ 60 days). If only the day is missing for either date or both dates, 
and the progression date and anticancer treatment end date corresponds to two 
consecutive months within the same year, then, the patient will be considered 
refractory, otherwise they will be considered not refractory. 
- 
Best overall response is SD or PD. 
- 
Reason for treatment discontinuation is “disease progression”. 
• Prior transplant: number (%) of patients with transplant, number (%) of transplant by 
patient (1, 2 and ≥3) 
• Prior surgery: number (%) of patients with any prior surgery and time from last surgery to 
first IMP administration (months) 
• Prior radiotherapy: number (%) of patients with any prior radiotherapy, intent (curative 
and palliative), type (systemic, internal beam, and external beam), and time from last 
radiotherapy to first IMP administration (months) 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5 
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All medications taken within 7 days prior to first dose of IMP, at any time during the treatment 
period, and up to 30 days after the last isatuximab administration are reported in the e-CRF. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version in effect at Sanofi (or the data management vender) at the time of the data base lock. 
• Prior medications are those the patient used prior to first isatuximab administration. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment phase.   
• Concomitant medications are any treatments received by the patient concomitantly to 
isatuximab, from first dose to the date of last administration + 30 days. A given 
medication can be classified both as a prior medication and as a concomitant medication.  
Concomitant medications do not include medications started during the post treatment 
period (as defined in the observation period in Section 2.1.4).  
• Post treatment medications (excluding post anticancer treatments) are those the patient 
took from 31 days after last isatuximab administration up to the end of the study. 
 
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Pre-medication 
Patients are to routinely receive pre-medications prior to isatuximab infusion to reduce the 
incidence and severity of hypersensitivity reactions. Pre-medications were defined in the protocol 
as non-IMP(s). The recommended pre-medication agents were: diphenhydramine 25-50 mg IV (or 
equivalent), methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent), 
and acetaminophen 650-1000 mg po 15-30 minutes (but no longer than 60 minutes) prior to 
isatuximab infusion. Analysis of pre-medications will focus on antihistamine, corticosteroids, h2 
blocker, and acetaminophen given (start and stop dates) on the days of isatuximab administrations. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Response assessments were to be performed on a monthly basis using IMWG criteria (Rajkumar. 
2011) and included: 
• M-protein quantification (serum and 24-hr urine) 
• Serum free light chain levels 
• Corrected serum calcium 
In case of plasmacytoma at baseline, radiological evaluations were to be performed every 3 cycles 
or when clinically indicated (i.e., to confirm a progression). 
In case of bone lesions at baseline, bone lesion evaluations were to be performed when clinically 
indicated or to confirm a response or progression. Bone marrow biopsy/aspiration was to be 
performed to confirm a sCR or CR. 
An independent adjudication committee (IAC) independently assessed clinical response using the 
IMWG response criteria. 
Biological responses (≥PR) and progression were to be confirmed on 2 consecutive biological 
(serum and/or urine M protein) disease assessments. No confirmation was required for 
radiological assessment. 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is ORR, defined as the proportion of patients with sCR, CR, VGPR 
or PR as best overall response (BOR) as assessed by the IAC. The BOR will be derived using 
disease assessments performed from the start of treatment through the entire study excluding any 
assessments performed after the cutoff date or following the start of further therapies for MM. 
The ordering of evaluations from best to worse is: sCR, CR, VGPR, PR, MR, stable disease (SD), 
progressive disease (PD), not evaluable (NE). BOR for patients without response assessment by 
the IAC will be ‘Not evaluable’. 
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Subgroup analyses of BOR using IAC assessment will be performed for the variables listed in 
Table 4. 
Table 4 – List of variables for subgroup analyses 
Variable 
Description 
Age 
<70 vs. ≥70 
Number of previous lines of therapy 
≤6 vs. >6 
Gender 
Male vs. Female 
ECOG PS 
0-1 vs. 2 
ISS staging at study entry 
I vs. II vs. III 
High risk cytogenetic 
Yes vs. No 
Baseline creatinine clearance 
<60 ml/min/1.73m2 vs. ≥60 ml/min/1.73m2 
With plasmacytomas at screening 
Yes vs. No 
 
2.1.3.2 Secondary efficacy endpoint(s) 
Secondary efficacy endpoints are defined below. 
• Duration of Response (DOR) (in weeks): DOR is defined as the time from the date of the 
first IAC determined response (≥ PR) that is subsequently confirmed, to the date of first 
IAC determined PD or death, whichever happens earlier (if reported before the analysis 
cut-off date or the date of initiation of a new anticancer treatment). If progression and 
death are not observed before the analysis cut-off date or the date of initiation of new 
anticancer treatment, DOR will be censored at the earliest of the date of the last valid 
disease assessment not showing disease progression performed prior to initiation of a 
further anticancer treatment or the analysis cut-off date. DOR is determined only for 
patients who have achieved a confirmed response of ≥PR. 
• Clinical benefit rate (CBR): defined as the proportion of patients with sCR, CR, VGPR, 
PR or MR as BOR according to IMWG criteria, as determined by the IAC. 
• Progression free survival (PFS) (in months): defined as the time interval from the date of 
first isatuximab administration to the date of the first IAC-confirmed disease progression 
or the date of death due to any cause, whichever comes first. For patients who did not 
experience IAC-confirmed disease progression and death before the analysis cut-off date 
of or the date of initiation of new anticancer treatment, PFS will be censored at the date of 
the last valid disease assessment not showing disease progression performed prior to 
initiation of a further anticancer treatment or the analysis cut-off date, whichever comes 
first.  
• Overall survival (OS) (in months): defined as the time interval from the date of first 
isatuximab administration to death from any cause. In the absence of the confirmation of 
death before the cut-off date, OS will be censored at the cut-off date or at the last date the 
patient is known to be alive, whichever comes first. 
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• Time to response (TTR) (in weeks): TTR is defined as the time from first dose to first IAC 
response (PR or better) that is subsequently confirmed. 
• Duration of follow-up (DFU) (in weeks): DFU is defined as the time from first dose to last 
response disease assessment before start of other therapy or cut-off date, whichever comes 
first. 
• Best percent change in paraprotein: best percent change in paraprotein will be calculated 
for the measurable paraprotein parameter defined at baseline excluding anytime point 
following the start of other anticancer therapy. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, 
such as clinical laboratory data, vital signs, ECG. 
Observation period 
The observation period will be divided into 3 periods: pre-treatment, on-treatment and post-
treatment. 
• 
The pre-treatment period is defined as the time from when the patients give informed 
consent and the start of isatuximab. 
• 
The on-treatment period is defined as the time from the first dose of isatuximab up to 30 
days after the last dose of isatuximab. 
• 
The post-treatment period is defined as the time from 31days after the last dose of 
isatuximab to the study closure. 
2.1.4.1 Adverse events variables 
Adverse events occurring from signature of informed consent form up to 30 days after the last 
isatuximab administration were to be recorded in the eCRF. 
All isatuximab related AEs and SAEs ongoing at time of study treatment discontinuation were to 
be followed during the follow-up period until resolution or stabilization. 
All AEs (including SAEs) will be 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 MedDRA in effect at Sanofi at the time of database lock. 
The severity of AEs was assessed according to NCI-CTCAE version 4.03. 
Adverse event observation period  
• 
Pre-treatment adverse events are adverse events that developed or worsened or became 
serious during pre-treatment period 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the on-treatment period 
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• 
Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period 
Other significant adverse events 
Other significant adverse events will include adverse events of special interest (AESIs), 
respiratory AEs, and specific hematological analyses. 
Adverse events of special interest 
The following AEs are considered adverse events of special interest: 
• Acute infusion associated reactions (IARs) 
• Symptomatic overdose 
• Pregnancy occurring in a female patient or in a female partner of a male patient 
Infusion associated reactions 
Infusion associated reactions, commonly observed with monoclonal antibodies, include AEs with 
onset date typically within 24 hours from the start of each isatuximab infusion (See Section 6.6 of 
the protocol for guidelines for IARs management). As described above, IARs are considered to be 
AESI. 
Two analyses of IARs will be performed. The first one will be based on the investigator’s 
reporting of IARs (i.e., as AESIs). For each IAR-AESI, the sites were instructed to report a 
generic term (infusion related reaction) and each individual symptom. For IAR analyses based on 
the generic term, a customized MedDRA query (CMQ) including the single preferred term of 
infusion related reaction will be used.  
The second analysis of IAR will include TEAEs occurring within 24 hours (one table including 
causally related TEAEs, one table including all TEAEs regardless of causal relationship) from the 
start of each isatuximab infusion (i.e., TEAEs with onset on the same calendar day of the 
isatuximab infusion or on the following day). 
Respiratory AEs 
Analysis of respiratory TEAEs will focus particularly on the groupings by CMQ. 
The respiratory AEs with onset during the post-treatment period will be analyzed separately, 
according to the same methods above. 
Hematological analyses (including both AE and laboratory neutropenia) 
Neutropenia (from laboratory abnormalities) will be displayed along with neutropenic 
complications (e.g., neutropenic infections, febrile neutropenia). 
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2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined in Section 2.1.4.  
• 
Death on-treatment: deaths occurring during the on-treatment 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, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken as defined in the study flow charts and as 
clinically indicated. The laboratory parameters will be classified as follows: 
• 
Hematology 
- 
Red blood cells, platelets and coagulation: hemoglobin, hematocrit, mean 
corpuscular volume, red blood cell count, platelet count, prothrombin time (expressed 
as international normalized ratio), activated partial thromboplastin time 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• 
Clinical chemistry 
- 
Metabolism: glucose, total protein, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium, corrected serum calcium, 
phosphate, magnesium  
- 
Renal function: creatinine, blood urea nitrogen, uric acid, e-GFR (revised equations 
for e-GFR in Japanese) 
- 
Liver parameters: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total and conjugated (direct) bilirubin 
- 
Pregnancy test: serum β-human chorionic gonadotropin (all female patients)  
- 
Hepatitis screen: hepatitis B surface antigen (HBs-Ag, HBc-Ab and HBs-Ab), HBV-
DNA, anti-hepatitis-C antibody (HCV-Ab) 
Urine samples will be collected as follows: 
- 
Urinalysis – quantitative: pH and specific gravity 
- 
Urinalysis – qualitative:  blood, ketones, bilirubin, leucocytes, nitrites, proteins and 
glucose 
Technical formulas are described in Section 2.5.1. 
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2.1.4.4 Vital signs variables 
Vital signs include: heart rate, respiratory rate, temperature, body weight, and systolic/diastolic 
blood pressure. 
2.1.4.5 Electrocardiogram variables 
Electrocardiogram variable include: 12 leads electrocardiogram and 2-D echocardiogram or 
MUGA scan. ECG was to be performed at screening and if clinically indicated. 
2.1.4.6 Other safety endpoints 
Other safety endpoints include: 
• Cytokines 
- 
TNF-α, IL-4, IL-6, IL-1-β, IFN-γ 
• IAR laboratory test 
- 
Complement (C3a, C4, CH50) 
- 
Serum tryptase 
• Chest X-ray at baseline and as clinically indicated. 
• Tumor lysis syndrome (TLS) 
2.1.5 Pharmacokinetic variables 
Isatuximab plasma concentrations will be summarized and the following PK individual 
parameters will be calculated: 
• Cumulative AUC over a 1, 2 or 4 week interval (AUC1W, AUC2W, AUC4W) 
• Ctrough (pre-dose concentration) at 1, 2, 4 weeks 
• Cmax at Cycle 1 Day 1, Cycle 2 Day 1 and Cycle 4 Day 1 
• Clearance (CL) 
• Accumulation ratios (AUCss/AUC1W). AUCss is AUC at steady state. 
2.1.6 Immunogenicity 
Human ADA to isatuximab was assessed during the study as defined in the protocol. 
Observation period 
The observation period will be divided into 2 periods: ADA pre-treatment and ADA on-study 
observation. 
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• 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 Cycle 10.  
Patients with at least one ADA result during the ADA on-study observation period will be 
considered evaluable for ADA. 
ADA attributes: 
• Pre-existing ADA is defined as ADA that was present in samples drawn during the ADA 
pretreatment period.  
• Treatment boosted ADA is defined as preexisting ADA with an increase in titer value 
between pre-treatment and post-treatment samples of at least two titer steps during the 
ADA on-study observation period. With a 2-fold serial dilution, this means that the post-
treatment sample titer value is at least (≥) 4 fold of pretreatment titer value.  
• Treatment-induced ADA is 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.  
• 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 ADA 
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 patient’s last sampling time point is ADA negative. 
• A 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 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between), OR 
- 
Treatment induced ADA detected in the last two sampling time points (both are 
positive), irrespective of the time period in between.  
- 
Indeterminate ADA is defined by treatment induced ADA detected only at the last 
sampling time point with all previous samples being negative  
 
ADA response endpoints: 
- 
An ADA positive patient is defined as a patient with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time during the on-study observation 
period 
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- 
ADA incidence is defined as the number of ADA positive patients among evaluable 
patients divided by the number of evaluable patients.  
- 
ADA prevalence is defined as the sum of the number of patients with preexisting 
ADA and the number of patients with treatment induced ADAs, divided by the number 
of evaluable patients. 
2.1.7 Biomarker endpoints 
2.1.7.1 Receptor density 
CD38 RD will be assessed from bone marrow aspirates at the screening. 
2.1.7.2 Immune genetic determinants 
Immune genetic determinants in peripheral blood plasma samples will be assessed at Cycle 1 Day 
1. 
2.1.7.3 Immune phenotyping 
Immune phenotyping in bone marrow (screening) and/or peripheral blood (Cycle 1 Day 1 and 
Cycle 3 Day 1) will be assessed. 
2.1.7.4 Soluble CD38 
Soluble CD38 levels in peripheral blood plasma samples will be assessed at Cycle 1 Day 1. 
2.1.8 Quality-of-life endpoints 
Not applicable 
2.1.9 Health economic endpoints 
Not applicable 
2.1.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies after discontinuation of IMP will be assessed. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
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Screened patients are defined as any patients who signed the informed consent. A listing of 
screening failure patients (screened patients who were not treated with isatuximab) and reason for 
screening failure (when available) will be provided. 
The number and percentage (when applicable) of patients in each of the following analysis 
population will be provided: 
• All treated/safety population 
• Pharmacokinetics population 
• ADA evaluable population 
For all above categories (except for the all treated population) percentages will be calculated using 
the number of patients in the all treated population. For the all treated population, no percentages 
will be calculated. 
For patient study status, the number and percentage of patients in each of the following categories 
will be provided using the all treated/safety population: 
• Patients off treatment and reasons for treatment discontinuation 
• Patients on treatment at time of the analysis cut-off date 
Major deviations potentially impacting efficacy/safety analyses include: 
• No prior treatment with IMiD and PI (for ≥2 cycles or ≥2 months of treatment) 
• Was not refractory to the most recently received both IMiD and PI included therapy 
• Did not achieve an MR or better to all prior lines of therapy 
All critical or major deviations will be summarized in a table giving numbers and percentages of 
patients with deviations. Protocol deviation will also be listed. 
2.2.1 Randomization and drug dispensing irregularities 
Not applicable, as this is non-randomized study. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 All treated/safety population 
The all treated/safety population will include all patients who have given their informed consent 
and who have received at least one dose (even incomplete) of isatuximab. 
This population is the primary population for the analyses of efficacy and safety parameters. All 
analyses using this population will be based on the treatment actually received. 
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2.3.2 Pharmacokinetic population 
The PK population will include patients from the safety population who receive at least 1 dose of 
isatuximab even if incomplete, with data for at least isatuximab concentration available post-
baseline. 
2.3.3 ADA evaluable population 
The ADA evaluable population will include all treated patients with at least one ADA assessment 
with a reportable during the ADA on-study observation periods 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of available data, mean, standard deviation, 
median, minimum, and maximum for each treatment group. Categorical and ordinal data will be 
summarized using the number and percentage of patients. 
Parameters described in Section 2.1.1 will be summarized using descriptive statistics.  
Past medical or surgical history other than multiple myeloma will be summarized by SOC (sorted 
by internationally agreed order) and PT (sorted by alphabetical order) for the all treated 
population. 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
Prior and concomitant medications will be presented for the all treated population. 
Medications will be summarized according to the WHO-DD, considering the first digit of the 
anatomical therapeutic chemical (ATC) class (anatomical 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 (anatomical or therapeutic) 
linked to the medication. Therefore, patients may be counted several times for the same 
medication. 
The table for prior and concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes. In case of equal frequency regarding ATCs, alphabetical 
order will be used. 
Pre-medications 
Number (%) of patients with pre-medications (antihistamine, corticosteroids, h2 blocker, and 
acetaminophen) will be summarized by each administration in cycle 1. 
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2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure will be assessed and summarized within the all treated population 
(Section 2.3.1). 
The dose information will be assessed by the following variables. 
• Number of cycles started 
• 
Duration of isatuximab exposure (or time on-treatment) in weeks is defined depending on 
the isatuximab administration schedule as follows: 
- 
If treatment is discontinued at a cycle with QW isatuximab administration: [date of last 
dose of isatuximab + 7 days – date of first dose of isatuximab] / 7. 
- 
If treatment is discontinued at a cycle with Q2W isatuximab administration:  [date of 
last dose of isatuximab + 14 days – date of first dose of isatuximab] / 7.  
• Actual dose in mg/kg: for a given cycle and day of administration, the actual dose in 
mg/kg corresponds to the actual dose in mg administered at this time point divided by the 
actual body weight as measured at each time point 
• Cumulative dose in mg/kg: the cumulative dose is the sum of all actual doses of 
isatuximab, expressed in mg/kg, given from first to last administration 
• Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) 
divided the duration of isatuximab exposure (in weeks) 
• Relative dose intensity (RDI) in %: 100 × ADI (mg/kg/week) / Planned Dose Intensity 
(mg/kg/week) 
Planned dose intensities corresponds to the planned dose (mg/kg) received at Day 1 of cycle 1, 
multiplied by the theoretical total number of doses during the started cycles (count 2 for Q2W and 
4 for QW), divided by the theoretical cycle duration expressed in weeks (i.e., 4 weeks), regardless 
of dose/schedule changes (as defined in the protocol section 6.5). ADI and RDI will be calculated 
separately in cycle 1 and subsequent cycles respectively, due to the difference of administration 
interval. 
Total number of cycles started, number of cycles started by patients as a quantitative variable and 
by category (i.e., number [%] of patients receiving at least 1 cycle, at least 2 cycles…), duration of 
isatuximab exposure, cumulative dose, ADI, RDI, and RDI by category (< 80%, [80 - 105%), 
≥105%) will be summarized by descriptive statistics. 
The following variables will be computed to describe dose delays and interruption: 
•  Cycle delayed is defined as follows: 
- 
A cycle is deemed as delayed if the start date of the current cycle - 28 - start date of the 
previous cycle is >3 days. Cycle delay is not defined for the first cycle. 
• Infusion delay (within a cycle, excluding day 1): within cycle 1, an infusion is deemed to 
be delayed if start date of the current administration – start date of previous administration 
– the theoretical duration (which is 7 days) is ≥3 days. For subsequent cycles (≥cycle 2), 
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an infusion is deemed to be delayed if start date of the current administration – start date 
of previous administration – the theoretical duration (which is 14 days) is ≥4 days 
• Dose interruption: A dose will be considered to be interrupted if the isatuximab 
administration is temporarily stopped during an infusion and then restarted (typically in 
case of Grade 2 IARs). 
• Dose reduction: Although not allowed in the study protocol, potential dose reductions will 
be screened and reported in the clinical study report. The first administration will not be 
counted as a dose reduction. For the second and subsequent isatuximab administrations, 
dose reduction will be determined using the dose level intervals provided in Table 5, by 
comparing the current dose level to the previous dose level. If the current dose level is not 
within the same dose level interval as the previous dose level, then the current dose level is 
considered reduced. 
Table 5 - Dose reduction criteria 
Actual dose level 
Dose level interval 
Dose level 1 (10 mg/kg) 
>0 mg/kg and ≤15 mg/kg 
Dose level 2 (20 mg/kg) 
>15 mg/kg and ≤25 mg/kg 
 
• Infusions not completed: patients who received less than 90% of the planned dose at an 
infusion. 
Dose delay and interruption will be analyzed at the patient, cycle, and total number of isatuximab 
administration levels as follows: 
• Patient level 
- 
Number of patients 
- 
Number (%) of patients with at least 1 dose reduction 
- 
Number (%) of patients with at least 1 dose interruption 
- 
Number (%) of patients with at least 2 infusions interrupted 
- 
Number of patients who could have a cycle delayed (patients who received ≥2 cycles, 
used for % calculation in this section): 
- 
Number (%) of patients with at least 1 cycle delayed 
- 
Number (%) of patients with a maximum cycle delayed between 4 and 7 days 
- 
Number (%) of patients with a maximum cycle delayed > 7 days 
- 
Number of patients who could have an infusion delay (patients who received ≥2 
infusions, used for % calculation in this section). 
- 
Number (%) of patients with at least 1 infusion delay. 
• Cycle level 
- 
Number of cycles administered (used for % calculation for this level) 
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- 
Number (%) of cycles delayed 
- 
Number (%) of cycles delayed with a maximum delay between 4 and 7 days 
- 
Number (%) of cycles delayed with a maximum delay on > 7 days 
• Total number of isatuximab administration level 
- 
Total number of isatuximab administration (used for % calculation for this level) 
- 
Number (%) of isatuximab administration interrupted 
- 
Number (%) of isatuximab infusions interrupted more than once 
- 
Number of infusion interrupted at (with % calculated using the total number of 
infusions interrupted): 1st infusion, 2nd infusion, subsequent infusions.  
- 
Time from infusion start to first interruption in minutes (quantitative (descriptive 
statistics) and qualitative: <5, 5–10, 11-30, 31–40, 41 –50, 51 –60, 61–90, 91–120, 
>120), missing.  
- 
Number (%) of infusions not completed (patients who received less than 90% of the 
planned dose). 
Duration of infusion is defined as the time from the start (date/time) of infusion to the end 
(date/time) of infusion. It will be summarized with descriptive statistics for first and subsequent 
infusions. A listing of dosing data will be provided and include the following variables, number of 
cycles started, cycle-day, start date, cycle delayed, actual dose in mg/kg, dose interruption, dose 
reduced and dose not complete. 
2.4.4 Analyses of efficacy endpoints 
All primary, secondary and exploratory analyses of efficacy endpoints will be performed using the 
all treated/safety population. 
2.4.4.1 Analysis of primary efficacy endpoint 
The primary analysis is based on the dose level determined as MTD combined in phase 1 and 
phase 2. ORR as assessed by IAC will be summarized. The null hypothesis that the true response 
rate (ORR) is <10% will be tested using a one-sided exact binomial test with a significance level 
of 0.025. A 95% two-sided confidence interval will be computed for ORR using Clopper-Pearson 
method. 
2.4.4.2 Analyses of secondary efficacy endpoints 
The following analyses will be performed. 
• A 95% two-sided confidence interval will be computed for CBR using Clopper-Pearson 
method. 
• OS and PFS will be analyzed by using the Kaplan-Meier method. The Kaplan-Meier 
estimates of the 25th, 50th and 75th percentiles and probability of surviving at every 4 
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months and the corresponding 95% confidence interval will also be computed. The 
Kaplan-Meier curves will be plotted. 
• DOR and TTR will be summarized with descriptive statistics for patients who achieve a 
response ≥ PR. 
• DFU will be summarized with descriptive statistics. 
• Paraprotein, the change and the percent change from baseline will be summarized with 
descriptive statistics for each cycle. Best percent change in paraprotein will be displayed in 
a waterfall plot. In the waterfall plot, patients with BOR of ≥PR will have negative 
percentage change. The patients will be ordered from highest positive change to smallest 
negative change. Percent change >100% will be displayed as 100% increases.  
• A swimmer plot of time on a treatment and a waterfall plot of best percent change in 
paraprotein will be provided. The patients will be ordered by BOR and duration of 
exposure. Patients with the best BOR and longest duration will be presented at the top of 
the plot. 
A listing of best percent change in % plasma cell in bone marrow biopsy will be provided and will 
include the following variables: measurable paraprotein at baseline, best percent change in 
paraprotein, BOR, baseline plasma cells count and post baseline plasma cells count (only for CR 
confirmation) and best percent change in plasma cells count. 
A listing of MRD negative patients will be provided (if any). 
 
2.4.4.3 Multiplicity issues 
Not applicable 
2.4.4.4 Additional efficacy analysis(es) 
Not applicable 
2.4.5 Analyses of safety data 
All safety analyses will be performed on the safety population as defined in Section 2.3.1, unless 
otherwise specified, the baseline value is defined as the last available value before the first 
isatuximab administration. 
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. 
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If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
the adverse event will be classified as pre-treatment, treatment-emergent, or post-treatment, 
according to the cycle number or visit of onset. The algorithm for imputing date of onset will be 
conservative and will classify an AE as treatment emergent unless there is definitive information 
to determine it is pretreatment or post-treatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5. 
The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same event during the observation period, the maximum grade is used. 
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 and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified. 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
Overview of TEAEs 
An overview of TEAEs including the number (%) of patients with the following events will be 
provided: 
- 
Treatment-emergent adverse event (TEAE) 
- 
Grade 3-5 TEAE 
- 
Drug-related TEAE 
- 
Grade 3-5 drug-related TEAE 
- 
Serious TEAE 
- 
Drug-related serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
AESI 
- 
Grade 3-5 AESI 
- 
Infusion associated reaction (excluding symptoms) 
- 
Grade 3-5 infusion associated reaction (excluding symptoms) 
Display of adverse events 
• All TEAEs by PT presented by all grades and grade≥3. 
• All TEAEs by primary SOC and PT presented by all grades and grade≥3. SOC will be 
sorted by internationally agreed order. PT will be sorted by decreasing order of frequency,  
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• All TEAEs by primary SOC, HLGT, HLT and PT, showing number (%) of patients with at 
least 1 treatment-emergent adverse event sorted by the SOC internationally agreed order. 
The other levels (HLGT, HLT and PT) will be presented in alphabetical order. 
• All drug-related TEAEs by PT presented by all grades and grade≥3. 
• All drug-related TEAEs by primary SOC and PT presented by all grades and grade≥3. 
Deaths, serious adverse events, adverse events leading to withdrawal, and other significant 
adverse events  
• 
Death: see Section 2.4.5.2. 
• 
Serious adverse events 
- 
All serious TEAEs by PT presented by all grades and grade≥3. 
- 
All serious TEAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 treatment-emergent adverse event. 
- 
All drug-related serious TEAEs related to isatuximab, by primary SOC and PT, 
showing the number (%) of patients with at least 1 treatment-emergent adverse event. 
- 
Listing of serious AEs. 
• TEAEs leading to treatment discontinuation 
- 
Summary of TEAEs leading to treatment discontinuation by SOC and PT. If the 
number of patients who discontinued treatment due to a TEAE is ≤ 5, no summary 
table will be provided. Instead, listing(s) will be provided.  
Other significant adverse events, including IARs, respiratory TEAEs, hematological adverse 
events, TEAE leading to dose modification, other AESI, pre- and post-treatment AE). 
• 
IAR-AESI (using the CMQ corresponding to the generic term of infusion related reaction 
reported by investigator as an AESI):  
- 
Analysis by patient: number of patients (used as denominator), worst grade by patient, 
number of episodes by patient (only 1 episode, ≥1 episode, ≥2 episodes, …. - an 
episode corresponds to a unique AE reference ID), first occurrence of IARs, patients 
with IAR at the first and/or subsequent isatuximab infusion, and number (%) of 
patients with at least 2 episodes of IARs at the same infusion.  
- 
Analysis by infusion: number of infusions (used as denominator), worst grade by 
infusion (a patient can have several IAR episodes at the same infusion). 
- 
Analysis by episode: number of episode (used as denominator), proportion of IARs 
occurring at each infusion, IAR duration, and day of onset. 
• 
IAR-AESI including symptoms as reported by investigator 
- 
Summary of IAR-AESI by SOC and PT,  
- 
Listing of IAR-AESI 
• 
Respiratory TEAEs:  
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- 
Lower respiratory TEAEs analyzed by IAR status (IAR or Non-IAR). 
- 
Respiratory infection TEAEs analyzed by IAR status (IAR or Non-IAR). 
In addition, late respiratory adverse events (i.e., occurring, worsening or becoming serious 
more than 30 days after last dose) will be analyzed as part of the post-treatment AEs 
analysis. 
• 
Hematological abnormalities (including analysis of both AE and laboratory neutropenia): 
- 
Number (%) of patients with neutropenia (from laboratory abnormalities) neutropenic 
infections and febrile neutropenia (from AE CMQs) by grade. 
• 
Summary of TEAEs leading to dose interruption of isatuximab, summary of TEAEs 
leading to dose reduction (if any), summary of TEAEs leading to dose delay.  
• 
Pregnancy and overdose being part of the AESIs, will be listed if observed. 
 
2.4.5.2 Deaths 
Number (%) of patients who died by study period (on-treatment and post-treatment) and within 60 
days from first dose of study treatment, and cause of death will be summarized. A listing of 
patients who died while participating in the study including cause of death, death date and days 
from first and last dose to death, preferred term, and causal relationship to isatuximab will be 
provided. 
2.4.5.3 Analyses of laboratory variables  
Each laboratory test result will be graded by NCI CTCAE (version 4.03), when applicable. 
Sponsor generic ranges are used for the grading of laboratory results, otherwise site ranges are 
used. For patients with multiple occurrences of the same laboratory variable during the on-
treatment period, the maximum grade (worst) per patient will be used.  
The number (%) of patients with abnormal laboratory tests at baseline and during the on-treatment 
period will be presented by all grades and each grade. At baseline, the last available value before 
or on the date of first study treatment administration (excluding repeated tests) will be used. 
Shift tables showing the number of patients in each grade at baseline by worst grade during the 
on-treatment period will be provided for selected laboratory tests. 
For creatinine clearance in mL per minute using MDRD formula (Revised equations for eGFR in 
Japanese), the number (%) of patients by category (<15, [15-30[, [30-60[, [60-90], >90) and by 
period (baseline and on-treatment) as well as a shift table will be provided. 
 
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2.4.5.4 Analyses of vital sign variables 
The incidence of potentially clinically significant abnormalities (PCSAs) (Table 6) at any time 
during the on-treatment period will be summarized. 
Table 6 - Potentially clinically significant abnormalities criteria for vital signs   
Parameter 
PCSA 
Comments 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
Temperature and respiratory rate will be summarized at baseline and end of treatment. 
A listing of vital signs will be provided. 
 
2.4.5.5 Analyses of electrocardiogram variables 
A listing of ECG results will be provided. 
2.4.5.6 Analyses of other safety endpoints 
ECOG PS and results of bone lesions and chest X-ray will be listed. 
The number (%) of patients with TLS reported under the TLS standard MedDRA query (SMQ) 
(i.e., haemorrhagic tumor necrosis, TLS, tumor necrosis) will be provided. Among those patients, 
the number (%) of patients with laboratory and clinical parameters which could be indicative of 
TLS prior to first dose and during the on-treatment period will also be provided.  
2.4.6 Analyses of pharmacokinetic 
2.4.6.1 Pharmacokinetic variables 
The population PK of isatuximab will be characterized in the population of patients using a 
nonlinear mixed effect modeling approach by MONOLIX software version 2016 R1 (or more 
recent version) (Lixoft). Both rich and sparse sampling PK data available from Phase 1, 2 and 
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possibly phase 3 studies will be used for the analysis. Additional details of the analysis plan 
(Population PK Analysis Plan) and the results will be provided in a separate document. The 
population estimates from this analysis will provide a prior distribution from which individual 
Bayesian estimates of the PK parameters and of individual exposure (Cmax, Ctrough and cumulated 
AUC) for each patient in this study will be derived.  
Pharmacokinetic parameters of isatuximab (listed in Section 2.1.5) will be summarized by 
descriptive statistics (such as mean, geometric mean, median, standard deviation, standard error of 
mean, coefficient of variation, minimum, and maximum).  
Predose dose concentration (Ctroughobs) of isatuximab will be tabulated with standard descriptive 
statistics by visit (up to Cycle 10) and will be represented graphically as function of sampling time 
(day/cycle) over the study period to visualize the steady state achievement. A listing of Ctroughobs 
for individual patients will also be provided. Ctroughobs will be kept for the descriptive statistics if 
sampling occurs after 7 days ± 2 days from previous infusion for sampling done until Cycle 1 Day 
22 and after 14 days ± 3 days from previous infusion for sampling done from Cycle 1 Day 22 up 
to Cycle 10.  
Cycles in patients with dose delay and/or dose reduction, and samples with missing date and/or 
time and/or date and time of the previous dose, will be discarded from the analyses. 
2.4.7 Immune response 
Using the ADA evaluable population, the number (%) of patients will be provided for the 
following if at least one positive observed: 
• Pre-existing ADA 
• ADA negative at baseline 
• On study ADA 
- 
Treatment-induced ADA 
- 
Persistent ADA 
- 
Transient ADA 
- 
Indeterminate ADA 
- 
Treatment boosted ADA 
- 
Last sample positive 
• ADA prevalence 
• ADA incidence 
In addition, a data listing of each ADA sample result will be provided. The impact on PK, safety 
and efficacy endpoints may be further explored by graphical methods or descriptive, depending on 
the ADA prevalence. 
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Statistical Analysis Plan  
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2.4.8 Analyses of Biomarker variables 
2.4.8.1 Receptor density 
CD38 RD will be summarized with descriptive statistics for responders/non-responders. A 
responder is a patient with IAC assessment response ≥ PR. In addition, summary of BOR will be 
provided by CD38 RD level and a graph showing ORR/non-responder rate (in y-axis) by CD38 
RD level (ranging from 0 to 500 000 by increment of 1000 in x-axis) will be provided. 
2.4.8.2 Genetic variables 
Summary of BOR will be provided for the following patients: 
• 
FcGR3A types: F/F, F/V, V/V and missing. 
• 
HLA and KIR genotypes including: 
- 
HLA-B BW4-80lle+ and KIR3DL1+ vs HLA-B BW4-80lle- or KIR3DL1-. 
- 
KIR3DS1- vs KIR3DS1+. 
2.4.8.3 Other variables  
Soluble CD38 will be summarized with descriptive statistics for responders/non-responders and 
listed. 
In addition, graphs showing responder/non-responder rate by biomarker levels will be provided 
for the following parameters at baseline: 
• 
Soluble CD38. 
• 
Immune cell level (B-cell, T-cell and NK-cell subsets respectively in blood and bone 
marrow samples). 
A listing of response data will be provided for patients with MRD. 
2.4.9 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapy for MM will be listed and not summary table will be provided. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
For the data censored at detection limits, its value will be substituted by DL/2. 
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Statistical Analysis Plan  
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2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. 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. 
For post anticancer treatments, if the anticancer treatment start date is missing, it will be imputed 
as follows: 
1. If the anticancer treatment start day is missing and the anticancer treatment start month 
and year are the same as the study treatment end month and year, the anticancer treatment 
start day will be set equal to the date of last study treatment administration + 1. 
2. If the anticancer treatment start day is missing and the anticancer treatment start month is 
not missing and the anticancer treatment start year is after the study treatment end year, the 
anticancer treatment start day will be set to 01. 
3. If the anticancer treatment start day is missing and the anticancer treatment start month is 
after the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01. 
4. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is the same as study treatment end year, the anticancer treatment start date will 
be set equal to the date of last study treatment administration + 1 
5. If the anticancer treatment start day and month are missing and the anticancer treatment 
start year is after the study treatment end year, the anticancer treatment start day and 
month will each be set to 01 
6. If the anticancer treatment start day is missing and anticancer treatment start month is 
before the study treatment end month and the anticancer treatment start year is the same as 
treatment end year, the anticancer treatment start day will be set to 01 
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Statistical Analysis Plan  
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Page 33 
7. If the anticancer treatment start day, start month and start year is missing, the anticancer 
treatment start date will be set equal to the treatment end date + 1. 
 
Handling of adverse events with missing/partial dates 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information or cycle/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. No imputation of adverse event end dates/times 
will be performed.  These data imputations are for categorization purpose only and will not be 
used in listings. No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events with missing grade 
Missing grades, if any, will be included 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 isatuximab is missing, then the relationship to isatuximab 
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. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information or cycle/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. No imputation of adverse event end dates/times 
will be performed.  These data imputations are for categorization purpose only and will not be 
used in listings. No imputation is planned for date/time of adverse event resolution. 
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2.5.4 Windows for time points 
An episode occurred during a cycle if the date of sampling is after the first date of the cycle, but 
prior or equal to the first day of the next cycle. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data and vital signs will be used for only 
computation of worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses 
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues 
Not applicable. 
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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3 
INTERIM ANALYSIS 
Not applicable. 
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Statistical Analysis Plan  
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Page 36 
4 
DATABASE LOCK 
The database lock is planned to be twice in phase 2. The cut off for the first database lock is at 
approximately 4 months after last patient first dosed. The cut off for the second database lock is at 
approximately 12 months after last patient first dosed. 
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Statistical Analysis Plan  
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
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6 
REFERENCES 
Not applicable. 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 39 
7 
LIST OF APPENDICES 
 
Appendix A: 
Sponsor generic ranges  
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Statistical Analysis Plan  
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Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 40 
Appendix A 
Sponsor generic ranges 
Table 7 - Hematological parameters  
LBTESTCD 
LBTEST 
GENDER
LBSTRESU
LBGNNRLO 
HGB 
Hemoglobin 
F 
g/L 
120 
HGB 
Hemoglobin 
M 
g/L 
135 
LYM 
Lymphocytes 
 
10^9/L 
1 
NEUT 
Neutrophils 
 
10^9/L 
1,8 
PLAT 
Platelets 
 
10^9/L 
150 
WBC 
Leukocytes 
 
10^9/L 
4,5 
EOS 
Eosinophils 
 
10^9/L 
0 
BASO 
Basophils 
 
10^9/L 
0 
MONO 
Monocytes 
 
10^9/L 
0,18 
HCT 
Hematocrit 
M 
% 
0,41 
HCT 
Hematocrit 
F 
% 
0,36 
RBC 
Erythrocytes 
F 
10^12/L 
4 
RBC 
Erythrocytes 
M 
10^12/L 
4,5 
INR 
 
 
Ratio 
0.8 
Table 8 - Biochemistry parameters  
LBTEST 
LBSTRESU
LBGNNRLO - LBGNNRHI 
Albumin 
g/L 
35 - 55 
Blood Urea Nitrogen (BUN) 
mmol/L 
3.6 – 7.1 
Coreccted calcium 
mmol/L 
2,2 - 2,6 
Chloride 
mmol/L 
80 - 115 
Glucose 
mmol/L 
3,9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 – 29 
Potassium 
mmol/L 
3,5 – 5 
Magnesium 
mmol/L 
0,8 - 1,2 
Sodium 
mmol/L 
136 – 145 
Phosphate 
mmol/L 
1 - 1,4 
Protein 
g/L 
55 – 80 
Urea 
mmol/L 
3,6 - 7,1 
 
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