Clinical trial NCT03594955
Conditions: Leukaemia
Sponsor: Sanofi
Start date: 2018-10-24; Completion date: 2021-02-06
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

* Dose escalation: To determine the maximum tolerated dose (MTD) of SAR440234 administered as a single agent in participants with relapsed or refractory acute myeloid leukemia (R/R AML), high risk myelodysplastic syndrome (HR-MDS), or B-cell acute lymphoblastic leukemia (B-ALL), and determine the recommended phase 2 dose (RP2D) for the subsequent Expansion part.
* Expansion part: To assess the activity of single agent SAR440234 at the RP2D in participants with R/R AML or HR-MDS.

Secondary Objective:

* To characterize the safety profile including cumulative adverse drug reactions.
* To evaluate the potential immunogenicity of SAR440234.
* To assess any preliminary evidence of hematologic response in the Dose Escalation Part.

Detailed description:
The duration of the study for the participants included a period for screening of up to 14 days. The cycle duration was 42 days. Participants continued study treatment as long as clinical benefit was possible or until disease progression, unacceptable adverse reaction, participant's decision to stop treatment, or other reason of discontinuation. After study treatment discontinuation participants returned to the study site 30 days after the last administration of SAR440234 for end of treatment assessments. Participants without documented disease progression at the end of a treatment visit who had not yet started treatment with another anti-cancer therapy would proceed with monthly follow-up visits until initiation of another anti-cancer therapy, disease progression, or study cut-off date, whichever came first.

Arms: arm 1: SAR440234 was administered as intravenous infusion once weekly for 6 weeks per Cycle. Per plan, participants were to receive first 2 to 3 doses as Lead-in doses followed by a fixed dose until the end of treatment or unless the dose needs to be decreased for safety reasons. Due to early study termination, all participants received only 1 treatment cycle at a dose of 1 nanogram per kilogram (ng/kg) once weekly.
Interventions: intervention 1: SAR440234
Intervention descriptions: intervention 1: Pharmaceutical form:lyophilisate to be resuspended in solution Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002378 VERSION N°5.0 (22-MAR-2017) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 
COMPOUND: SAR440234 
An open-label, first-in-human, dose escalation study of SAR440234 administered 
as single agent by intravenous infusion in patients with relapsed or refractory 
acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia (B-ALL), 
or high risk myelodysplasia (HR-MDS) 
STUDY NUMBER: TED15138 
VERSION DATE / STATUS: Approval date (29-Aug-2019) / Approved 
Version Number: 
2 
EudraCT 
2017-004148-39 
IND Number(s) 
13420 
WHO universal trial number 
U1111-1197-8041 
Date: 
29-Aug-2019
Total number of pages: 
143 
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NAMES AND ADDRESSES OF  
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
Company: 
Address: 
 
 
 
Tel: 
Fax: 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, Version 
Amended Protocol 03 
All 
29 August 2019, Version number: 2 (electronic 8.0) 
Amended Protocol 03 
All 
11 July 2019, Version number: 1 (electronic 7.0) 
Amended Protocol 02 
All 
15 February 2019, Version number: 1 (electronic 6.0) 
Amended Protocol 01 
All 
29 May 2018, Version number: 1 (electronic 4.0) 
Amendment 01 
All 
29 May 2018, Version number: 1 (electronic 4.0) 
Original Protocol 
All 
22 November 2017, Version number: 1 (electronic 2.0) 
Amended protocol 03 (29-Aug-2019) 
This amended protocol (Amendment 3) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this amended protocol is to replace the first 3 patients treated during the Dose 
Escalation Part because of uncertainties in the doses that they received and to restart the study at 
dose level 1 using a 3+3 design, following resolution of the full clinical hold.  
In addition, minor editorial corrections (especially for consistency and clarity) have been made. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Tabular Summary “Statistical 
Considerations”, Section 6.3, 
Section 11.2, and 
Section 13.1.1 
The following sentence has been added: The first 3 
patients treated during the Dose Escalation Part will be 
replaced.  Another 3 patients will be enrolled in dose 
level 1 and the trial will proceed according to the 3+3 
design. 
Text was added to clarify that the 
first 3 patients treated during the 
Dose Escalation Part will be 
replaced because abnormalities 
were detected in their 
pharmacokinetic profiles. These 
findings suggest that these patients 
may have received unintentional 
overdoses of SAR440234 on some 
occasions. Data from these patients 
will be used as part of the safety 
database but will not be used for 
dose escalation decision. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.2.1 
The following text was modified:  Within a dose level, 
subsequent patients will initiate treatment at least 1 week 
after the first patient in that dose level started treatment 
with SAR440234. 
Clarification to be consistent with 
Clinical Trial Summary. 
Tabular Summary, 
Sections 6.2.1, Section 6.2.2,  
and Table 3  
The following text was modified: Two A 3+3 dose 
escalation scheme (accelerated in DL1 and DL2), then 
3 + 3 escalation (DL ≥3)  will be used, based on DLTs 
observed during the first 42 days following the first 
administration of IMP in the first cycle (the DLT 
observation period).The goal is to treat 1 patient 3 
patients per dose level at DL1 and DL2 (accelerated part) 
unless any Grade 2 or higher AE occurs, in which case 3 
patients will be included in order to follow a 3 + 3 design. 
DL3 to DL8 will include 3 patients per dose level. 
To improve the ability to detect 
safety signals accurately, the Dose 
Escalation Part will now follow a 3+3 
trial design, rather than an 
accelerated design. 
Section 13.3.2 
The following sentence has been added: The first 3 
patients treated will be excluded from the DLT-evaluable 
population. 
Flow Chart Table 1.2.1, 
Table 1.2.2, Table 1.2.3, and 
Table 1.2.4 
The following sentence has been added to the footnote 
concerning SAR440234 administration: Specific details 
about SAR440234 preparation and administration are 
provided in the Pharmacy Manual. 
Text was added to draw attention to 
the importance of referring to the 
Pharmacy Manual regarding details 
of SAR440234 preparation and 
administration. 
Throughout 
Correction of formatting, typographical errors and 
standardization of wording. 
To increase clarity 
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CLINICAL TRIAL SUMMARY  
COMPOUND: SAR440234 
STUDY No: TED15138 
TITLE 
An open-label, first-in-human, dose-escalation study of SAR440234 administered as 
single agent by intravenous infusion in patients with relapsed or refractory acute 
myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia (B-ALL) or high 
risk-myelodysplasia (HR-MDS) 
INVESTIGATOR/TRIAL LOCATION 
United States (US), European Union (EU), Asia 
PHASE OF DEVELOPMENT 
Phase 1/2A 
STUDY OBJECTIVES 
 
Primary objectives: 
 
Dose Escalation Part: To determine the maximum tolerated dose 
(MTD)/maximum administered dose (MAD) of SAR440234 administered as 
a single agent in patients with R/R AML, HR-MDS, or B-ALL, and determine 
the recommended Phase 2 dose (RP2D) for the subsequent Expansion 
Part. 
 
Expansion Part: To assess the activity of single agent SAR440234 at the 
RP2D in patients with R/R AML, or HR-MDS. 
Secondary objectives: 
 
To characterize the safety profile of SAR440234 including cumulative 
adverse drug reactions. 
 
To characterize the pharmacokinetic profile of SAR440234 when 
administered as a single agent.  
 
To evaluate the potential immunogenicity of SAR440234.  
 
To assess any preliminary evidence of hematologic response in the Dose 
Escalation Part.  
Exploratory objectives:  
To perform pharmacodynamic assessments on blood and bone marrow including: 
 
To measure CD123 expression in malignant cells and kinetics of this 
expression under treatment.  
 
To monitor CD123 expression on normal cells. 
 
To assess minimal residual disease (MRD) in patients achieving a complete 
response (CR) or complete response with incomplete hematological 
recovery (CRi), and correlate MRD with clinical outcome. 
 
To assess T-cell subpopulations (eg, CD4, CD8) and activation status. 
 
To investigate the relationship between CD123 expression, disease 
molecular subtype (as defined by marker expression, cytogenetics, and/or 
genomics) and parameters of clinical response. 
To assess levels of cytokines following treatment administration, and their 
relationship with safety profile and clinical outcome. 
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STUDY DESIGN 
This Phase 1/2A study is an open-label, nonrandomized, dose escalation and 
dose expansion, safety, efficacy, pharmacokinetic, and pharmacodynamic 
evaluation study of SAR440234 administered as a single agent intravenous (IV) 
infusion every week to patients ≥16 years of age with R/R AML, HR-MDS, or 
B-ALL. 
Dose Escalation Part 
The administration of the investigational medicinal product (IMP) will begin at 
1 ng/kg, representing the selected safe starting dose for a first-in-human (FIH) 
trial, based on the Minimal Anticipated Biological Effect Level (MABEL), and by 
integration of all available in vivo and in vitro data at the start of the study.  
A 3+3 dose escalation scheme will be used, based on dose-limiting toxicities 
(DLTs) observed during the first 42 days following the first administration of the 
first cycle of treatment. Adverse events (AEs) will be graded according to the 
National Cancer Institute (NCI) common terminology criteria (CTC) for AEs 
(NCI-CTCAE) v4.03, except for cytokine release syndrome (CRS), which will be 
graded according to the 2014 NCI Consensus Guidelines. 
In this FIH study, potential DLTs are defined as the following: 
 
Any Grade ≥3 nonhematological AE, unless either caused by disease 
progression or obviously unrelated cause or caused by a laboratory 
abnormality without associated clinical consequences that resolves within 
5 days (AE’s related to cytopenias that were present prior to starting 
SAR440234 or to underlying leukemia will not be considered DLT’s).  
 
Grade 4 hematological toxicities, ie, new onset or worsening of 
life-threatening hematological abnormalities after administration of 
SAR440234. (AE’s related to cytopenias that were present prior to starting 
SAR440234 or to underlying leukemia will not be considered DLT’s.): 
- 
Grade 4 bone marrow hypocellularity, if not caused by disease 
progression and not improved to baseline value or Grade ≤1 within 
14 days, 
- 
Grade 4 decreased neutrophils, if not present at baseline and not 
resolved to baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 febrile neutropenia not resolved within 7 days, 
- 
Grade 4 decreased platelet count, if not present at baseline and not 
improved to baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 anemia, if not improved to baseline value or Grade ≤1 within 
14 days. 
 
Grade 3 or Grade 4 CRS. 
 
Grade 2 CRS if it persists for >48 hours or is present <48 hours before the 
time when the next planned dose of SAR440234 is due. 
 
Any treatment-emergent adverse event (TEAE) that, in the opinion of the 
Principal Investigator and Sponsor, is of potential clinical significance such 
that further dose escalation would expose patients to unacceptable risk. 
 
IMP-related adverse reaction (unless caused by disease progression or an 
obviously unrelated cause) lasting more than 2 weeks with failure to recover 
to baseline or improve to Grade ≤1. 
The occurrence of DLTs will inform the dose recommendation that will be used 
during the Expansion Part. 
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Response assessment will be performed according to the International Working 
Group (IWG) 2003 recommendations for AML, the revised 2000 criteria for 
HR-MDS and the 2016 National Comprehensive Cancer Network (NCCN) 
Guidelines for ALL.  
If at the end of a cycle the patient exhibits clinical benefit by symptoms or 
response criteria and does not meet study treatment discontinuation criteria, the 
patient may continue therapy until an unacceptable AE, disease progression, 
patient's decision to stop the treatment, or any other reason. 
To minimize the risk of severe CRS, an intra-patient dose escalation in Cycle 1 is 
proposed, as shown in Table 1. Lead-in doses include the first 2 doses in Dose 
Level (DL) 1 and DL2 (ie, Week 1 and Week 2 administered doses), the first 
3 doses in DL3 to DL5, and the first 4 doses in DL6 to DL8. After the lead-in 
doses, each patient will receive a fixed dose until the end of treatment, unless the 
dose needs to be decreased for safety reasons. DL1 to DL8 will achieve a range 
of lead-in doses from 
 and a range of final doses from 
 
. During Cycle 1 and Cycle 2, pharmacokinetic and pharmacodynamic 
data will be collected that will be used, together with acute safety monitoring, to 
inform the choice of subsequent dose levels for both the Dose Escalation Part and 
the Expansion Part. 
Table 1 
Dose 
Level 
Cycle 1 (doses in ng/kg) 
W1 
W2 
W3 
W4 
W5 
W6 
D1 
D4 
D8 
D15 
D22 
D29 
D36 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
DL8 
D=Day, W=Week 
For subsequent cycles, patients will maintain the maximum weekly dose that they 
achieved in Cycle 1, as shown in Table 2. 
Table 2 
Dose 
Level 
Cycle ≥2 (doses in ng/kg) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
DL8 
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Dose-limiting toxicity  
The DLT observation period is 42 days from the first administration of IMP in the 
first cycle, with administration on Day 1, Day 4 (DL ≥3), Day 8, and weekly 
thereafter. A new dose level may begin after the DLT observation period of the 
previous dose level is finished. The goal is to treat 3 patients per dose level in 
order to follow a 3 + 3 design. DL3 to DL8 will include 3 patients per dose level. In 
the event of a DLT, the dose level will be expanded to a total of 6 patients, who 
will be treated at the same dose level that the DLT occurred (3 + 3 design). If 1 of 
the 6 patients experience an IMP-related DLT at the dose level, the dose 
escalation will proceed with 3 patients per dose level. If >2 of 6 patients 
experience an IMP-related DLT, the MAD has been reached and the dose 
escalation will be stopped. 
Inclusion of B-ALL patients  
At any DL ≥3, patients with B-ALL (see inclusion criterion I 01) may also be 
recruited in the Dose Escalation Part.  
Study continuation 
The duration of each cycle of treatment is 42 days, with weekly administration of IMP 
(except for Cycle 1 Week 1 in DL ≥3 when 2 administrations will be given). 
In the Dose Escalation Part, at the end of Cycle 1, 43 days after the first 
SAR440234 infusion, a patient may begin Cycle 2 provided he or she did not 
experience a DLT. The dose given in the second or subsequent cycles will be the 
last dose given in the previous cycle.  
If severe toxicity occurs, dose reduction, omission, treatment delay, and/or 
treatment discontinuation are planned (details are provided in Section 6.5). 
A Study Committee, including the main Investigators, Sponsor clinical team, and 
ad hoc experts, when appropriate, will regularly review the safety data, and will 
make recommendations as appropriate.  
Additional (optional) cohort(s) beyond DL8, or intermediate dose levels, may be 
evaluated; the decision to proceed with these optional cohort(s), however, will be 
discussed with the Study Committee and based on the available safety, 
exploratory, and pharmacokinetic data.  
Maximum tolerated dose 
The MTD will be defined as the highest dose level at which no more than 1 patient 
of a maximum of 6 patients experienced an IMP-related DLT.  
Expansion Part 
The Study Committee will decide the RP2D, including the recommended lead-in 
dose and schedule, for the Expansion Part in R/R AML and HR-MDS patients. The 
expected total enrollment for the Expansion Part is 37 patients, all treated at the 
RP2D, to evaluate further the safety, pharmacokinetics, and possible disease 
response. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. 
Confirmed diagnosis of primary or secondary AML (any subtype except 
acute promyelocytic leukemia) according to World Health Organization 
(WHO) classification, or myelodysplastic syndrome (MDS) with a revised 
International Prognostic Scoring System (R-IPSS) risk category of 
intermediate or higher. Patients must have exhausted available 
treatment options and must not be eligible for any treatment known to 
provide clinical benefit. 
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I 02. 
Patients with AML must have relapsed or refractory disease that has been 
resistant to available therapies, as defined by any 1 of the following criteria: 
- 
Leukemia refractory to ≥2 intensive remission induction attempts, 
- 
Leukemia in first relapse within 1 year following allogeneic stem cell 
transplant, 
- 
Leukemia in second or higher relapse, 
- 
Not eligible for intensive remission induction therapy and have 
persistent leukemia despite ≥2 cycles of therapy, including any of the 
following: hypomethylating agent (eg, decitabine or 5-azacitidine), 
chemotherapy, or targeted agents (eg, gemtuzumab ozogamicin or 
enasidenib). 
I 03. 
During the Dose Escalation Part, patients with B-ALL without 
extramedullary lesions, in second or subsequent relapse, may also be 
recruited at any DL ≥3 during the 3 + 3 escalation period. B-ALL patients 
should have completed previously ≥1 cycle of a salvage regimen, 
including any of the following: chemotherapy, blinatumomab, tyrosine 
kinase inhibitors, cellular therapy (eg, tisagenlecleucel), or targeted 
agents (eg, inotuzumab ozogamicin). Patients must have exhausted 
available treatment options and must not be eligible for any treatment 
known to provide clinical benefit. 
I 04. 
Patients with HR-MDS must have >10% blasts in the bone marrow at the 
time of enrollment and fit one of the following categories: 
- 
Not eligible for induction therapy and having completed ≥2 cycles of 
therapy, including any of the following: hypomethylating agent (eg, 
5-azacitidine or decitabine), chemotherapy, or targeted agents. 
- 
Not eligible for allogeneic stem cell transplant and having completed 
≥1 course of induction therapy. 
I 05. 
Signed written informed consent. 
 
Exclusion criteria: 
E 01. 
Age <16 years old.  
E 02. 
Eastern Cooperative Oncology Group (ECOG) performance status >2. 
E 03. 
Abnormal laboratory parameters, including the following: 
- 
Total bilirubin >1.5 x upper limit of normal (ULN), unless Gilbert’s 
syndrome is present, 
- 
Alanine aminotransferase, aspartate aminotransferase or alkaline 
phosphatase >2.5 x ULN, 
- 
Serum creatinine >2 x ULN and/or creatinine clearance <30 mL/min, 
- 
Grade 4 hematological toxicity: febrile neutropenia, bone marrow 
hypocellularity, symptomatic disseminated intravascular coagulation, 
life-threatening anemia, or life-threatening thrombotic 
thrombocytopenic purpura, 
- 
White blood cell count > 30,000/mm3.  
- 
If the white blood count exceeds 30,000/mm3, hydroxyurea may be 
used to reduce the white blood cell count to < 30,000/ mm3 at start of 
treatment. 
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- 
Hydroxyurea may be administered at the investigator’s discretion 
during Cycle 1, but must be stopped ≥1 day prior to Cycle 2, Day 1. 
E 04. 
Graft-versus-host disease following allogeneic stem cell transplantation 
requiring treatment with more than 10 mg of oral prednisone or equivalent 
daily. The stem cell transplant and/or donor lymphocyte infusion should have 
been performed more than 3 months before study treatment start. 
E 05. 
History of an active or chronic autoimmune condition that has required or 
requires therapy. 
E 06. 
Prior treatment with an anti-CD123-directed agent. 
E 07. 
Second primary malignancy that requires active therapy. Adjuvant hormonal 
therapy is allowed. 
E 08. 
Previous treatment with chemotherapy, radiotherapy, or immunotherapeutic 
agents in the 4 weeks prior to IMP administration (Cycle 1 Day 1), except for 
hydroxyurea. 
E 09. 
Previous treatment with any other investigational agent in the 4 weeks prior 
to IMP administration (Cycle 1 Day 1). 
E 10. 
Receiving at the time of first IMP administration concurrent steroids 
>10 mg/day of oral prednisone or the equivalent for ≥3 months, except 
steroid inhaler, nasal spray or ophthalmic solution. 
E 11. 
Requirement for tocilizumab for any other diagnosis within ≤14 days before 
the first administration of SAR440234.  
E 12. 
Known contraindication to any of the noninvestigational medicinal products 
(NIMPs) (dexamethasone and tocilizumab), acetaminophen, 
diphenhydramine, ranitidine, montelukast or similar agents. 
E 13. 
Evidence of active central nervous system leukemia at the time of 
enrollment. 
E 14. 
Known acquired immunodeficiency syndrome (AIDS-related illnesses) or HIV 
disease requiring antiretroviral treatment, or having active hepatitis A, B or C 
infection, or tuberculosis. 
E 15. 
Pregnant and breast-feeding women, female patients of childbearing 
potential, and male patients with female partners of childbearing potential 
who are not willing to avoid pregnancy by using an adequate method of 
contraception (2 barrier method or 1 barrier method with a spermicide, 
intrauterine device, or hormonal contraception with inhibition of ovulation, for 
2 weeks prior to the first dose of SAR440234, during treatment, and 
12 weeks after the last dose of study treatment). A woman is considered of 
childbearing potential, ie, fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. 
E 16. 
Any country-related specific regulation that would prevent the patient from 
entering the study.  
E 17. 
Any clinically significant, uncontrolled medical conditions that, in the 
Investigator's opinion, would expose excessive risk to the patient or may 
interfere with compliance or interpretation of the study results. 
E 18. 
Patients weighing <60 kg (DL1, DL2, and DL3 only). 
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Total expected number of patients 
It is expected that a total of 67 to 77 patients will be enrolled. It is anticipated that 
30 to 40 patients will be enrolled in the Dose Escalation Part, and up to 
37 patients will be enrolled in the Expansion Part.  
Expected number of sites 
Up to 4 sites in the Dose Escalation Part, in France and the United States. 
Up to 14 sites in the Expansion Part in Europe, the United States, and Asia. 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s)  
 
Formulation: 
SAR440234 
The drug product is presented as a lyophilisate powder for solution for IV injection at 
 The concentration 
 after reconstitution with water for 
injection. 
Route of administration: 
IV 
Dose regimen: 
SAR440234 will be administered IV every 7 days (except for Cycle 1 Week 1 in 
DL ≥3 when 2 administrations will be given) for a 42-day cycle. Cycles run 
consecutively so that Day 1 of each cycle is normally 7 days after the start of the last 
infusion in the previous cycle.  
The dosing regimen will be weight-based; however, if a patient weighs >140 kg, the 
patient's weight will be capped at 140 kg for dose calculations. The patient may 
continue to receive therapy provided he or she continues to have clinical benefit and 
does not meet the stopping criteria. 
The dose is defined by dose level rule during the Dose Escalation Part and by the 
selected dose in the Expansion Part. 
During the Dose Escalation Part, escalation to the next dose level cohort will occur 
after the last patient has completed the DLT observation period for the previous 
dose level. Within a dose level, subsequent patients will initiate treatment at least 
one week after the first patient in that dose level started treatment with 
SAR440234. 
Noninvestigational medicinal 
products 
 
Formulation: 
Dexamethasone: 4 mg/mL for IV injection. 
Tocilizumab: 200 mg/10 mL vial 
Montelukast: 10 mg tablets 
Routes of administration: 
IV (dexamethasone), IV (tocilizumab), oral (montelukast) 
Dose regimen: 
 
Dexamethasone 20 mg IV will be instituted as systematic premedication 4 hours 
and 1 hour prior to each IMP administration.  
Montelukast 10 mg oral (PO) will be given once, 4 hours before the start of 
SAR440234 infusion.  
Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if 
CRS Grade 2 has occurred in a previous patient or previous administration in the 
same patient. This rule will be applied for the same patient who experienced a 
CRS event for subsequent infusions and for all patients subsequently enrolled at 
that dose level or higher.  
For each patient treated, the clinical site must have at least 2 full doses of 
tocilizumab in the clinical pharmacy ready for immediate administration in case of 
CRS Grade 2 or above. For patients with Grade 2 CRS, tocilizumab will be 
administered at 8 mg/kg infused over 1 hour for patients weighing ≥30 kg 
(maximum dose 800 mg) or 12 mg/kg infused over 1 hour for patients weighing 
<30 kg. If there is insufficient improvement in CRS within 12 hours, tocilizumab 
may be repeated at the same dose every 12 hours for a total of 3 doses. 
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Tocilizumab must not be used for prophylaxis of CRS. 
Patients with Grade 3 or Grade 4 CRS should be treated with tocilizumab as for 
patients with Grade 2 CRS.  
For patients with Grade 3 or Grade 4 CRS who do not respond to tocilizumab 
within 24 hours, dexamethasone 10 mg IV should be given every 6 hours. 
ENDPOINTS 
 
Primary endpoints: 
With an objective of defining the RP2D and dose schedule, the safety of SAR440234 
will be evaluated using the following assessments during the Dose Escalation Part: 
 
Incidence of DLT observed during the first 42 days following the first 
administration of IMP in the first cycle of treatment. 
 
Incidence of allergic reactions/hypersensitivity and CRS/acute infusion 
reactions. 
In the Expansion Part, disease response for R/R AML and HR-MDS will be an 
additional primary endpoint: 
 
Preliminary anti-leukemia activity as defined by the IWG for MDS or AML: 
- 
Overall response rate (ORR) including CR, CRi, and partial 
response, 
- 
Duration of response, 
- 
Event-free survival. 
Secondary endpoints: 
 
The safety profile of SAR440234 in terms of TEAEs, serious adverse events 
(SAEs), and changes in laboratory parameters, vital signs, 
electrocardiograms (ECGs), and assessment of physical examination. 
 
Pharmacokinetic parameters of SAR440234: Concentration observed at the 
end of IV infusion, maximum concentration observed (Cmax), time to reach 
Cmax, last concentration observed above the lower limit of quantification, time 
of the last concentration observed above the lower limit of quantification (ie, 
Clast), concentration observed just before treatment administration during 
repeated dosing, area under the plasma concentration versus time curve 
(AUC) calculated using the trapezoidal method from time zero to Clast, AUC 
calculated using the trapezoidal method from time zero to infinity, AUC 
calculated using the trapezoidal method over the dosing interval (7 days). 
 
Incidence rate of anti-drug antibody (ADA, ie, anti-SAR440234 antibody) 
development. 
 
In the Dose Escalation Part, preliminary anti-leukemia activity as defined by 
IWG for MDS or AML, or NCCN for B-ALL. 
Exploratory endpoints:  
 
Assessment of CD123 expression in cells in the peripheral blood and bone 
marrow aspirate. Percentage of CD123-expressing cells may be a 
pharmacodynamic biomarker for response to the IMP.  
 
Monitoring of T-cell subpopulations (eg, CD4, CD8) and activation status in 
the peripheral blood and bone marrow aspirate.  
 
Minimal residual disease by molecular biology assessment and/or flow 
cytometry will be assessed in bone marrow from patients achieving a CR or 
CRi and correlated with clinical outcome. 
 
Assessment of plasma cytokine levels in blood at specific time points 
following treatment administration to evaluate potential associations of 
cytokine levels with safety and clinical outcomes. 
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ASSESSMENT SCHEDULE 
See Section 1.2 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
It is anticipated that approximately 72 patients (67 to 77 patients) will be enrolled 
in this study (Dose Escalation and Expansion Parts).  
Dose Escalation Part 
It is anticipated that approximately 30 to 40 DLT-evaluable patients will be entered 
in the Dose Escalation Part. The actual sample size will vary depending on DLTs 
observed and number of dose levels actually explored. 
 
Any patient who is not evaluable for DLT, ie, who discontinues the study treatment 
before the end of Cycle 1 for any reason other than DLT, or who did not receive 
treatment as planned, will be replaced. The first 3 patients treated during the Dose 
Escalation Part of TED15138 will be replaced. Another 3 patients will be enrolled 
in DL1 and the trial will proceed according to the 3+3 design. 
Expansion Part 
It is hypothesized that SAR440234 would induce a response rate of 40% and that 
the null hypothesis for ORR is 20%. Under these hypotheses and using a 
Simon 2-stage design (optimal), with a 1-sided 10% significance level and a power 
of 90%, it is planned to enroll 37 patients in the Expansion Part of the study. 
Eleven (11) responses out of 37 patients will be necessary to reject the null 
hypothesis (H0 response rate = 20%).  
An interim analysis of the ORR will be done after treatment of the first 17 patients 
through 2 cycles. If 3 or fewer responses (CR, CRi, or PR) are observed, the 
Expansion Part will be stopped due to futility.  
Analysis population: 
The DLT-evaluable population in the Dose Escalation Part will include all patients 
who have received at least 5 out of 6, weekly IV administrations of SAR440234 in 
DL1 and DL2, patients who have received at least 6 out of 7 IV administrations of 
SAR440234 in DL ≥3, and patients who discontinue the IMP before completion of 
Cycle 1 because of a DLT.  
The all-treated/safety population for both Dose Escalation and Expansion Parts of 
the study will include all patients who have given their informed consent and who 
have received at least 1 dose (even incomplete) of SAR440234. 
Response evaluable patients are defined as patients from the all-treated/safety 
population with at least 1 post-baseline evaluable disease assessment allowing 
status evaluation. 
The ADA (ie, anti-SAR440234 antibody) population will include all patients from 
the all-treated/safety population with at least 1 available ADA result after 
IMP administration. 
The pharmacokinetic population will include patients from the all-treated/safety 
population with at least 1 evaluable drug concentration after IMP administration 
(whatever the cycle and even if incomplete). 
Safety and dose escalation primary analysis: 
DLTs occurring during the DLT observation period will be analyzed in the 
DLT-evaluable population. Adverse events meeting DLT criteria occurring at any 
additional cycle will be assessed and analyzed in the all-treated/safety population.  
Pharmacokinetic parameters will be summarized with descriptive statistics. Dose 
proportionality and accumulation will also be assessed on relevant parameters in 
the pharmacokinetic population. 
The safety profile will be summarized for all the treated patients, as well as 
separately, in the Dose Escalation Part and Expansion Part. 
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Efficacy analyses in the expansion cohort 
The ORR and other efficacy will be summarized using descriptive statistics. A 95% 
2-sided confidence interval will be computed for ORR using the Clopper-Pearson 
method. 
DURATION OF STUDY PERIOD (per 
patient)  
The duration of the study for a patient will include a period for screening of up to 
14 days. The cycle duration is 42 days. After study treatment discontinuation, 
patients will return to the study site 30 days after the last IMP administration for 
end of treatment assessments. 
Patients may continue treatment with the IMP as long as clinical benefit is 
possible, or until disease progression, unacceptable adverse reaction, patient’s 
decision to stop treatment, or other reason for discontinuation. During the 
follow-up period, IMP-related AEs and all SAEs (regardless of relationship to study 
treatment) present at the time of study treatment discontinuation will be followed 
every month until resolution or stabilization, or until initiation of another 
antineoplastic therapy. 
Patients without documented disease progression at the end of a treatment visit 
who have not yet started treatment with another anti-cancer therapy will proceed 
with monthly follow-up visits until initiation of another anti-cancer therapy, disease 
progression, study cut-off date, or death, whichever comes first. 
The first cut-off date will be at the end of the first cycle of the last patient treated in 
the Dose Escalation Part in order to have at least the first cycle evaluable for all 
patients for determination of the MTD and for the RP2D. 
The second cut-off date will be when the last patient in the Expansion Part will 
have been treated for 2 cycles (approximately 3 months), or has early progression, 
whichever occurs first, in order to assess tumor response. After the second cut-off 
date, ongoing patients will receive study treatment until disease progression or 
occurrence of an AE leading to treatment discontinuation, whichever is earlier, and 
they will only be followed for study treatment administration, SAEs, study 
treatment-related AEs, and reason for end of treatment. 
 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
 
 
 
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1.2 
STUDY FLOW CHARTS  
1.2.1 Dose Escalation Part: Screening and Treatment Cycle 1  
Evaluation a 
Screening 
Treatment Cycle 1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
D-14 to 
D-1 
D1b D2, D3 
D4 
D5, 
D6, D7 
D8 
D9 
D10, 
D11 
D12, 
D13, 
D14 
D15 
D16, 
D17, 
D18 
D19, 
D20, 
D21 
D22 
D23, 
D24, 
D25 
D26, 
D27, 
D28 
D29 
D30, 
D31, 
D32 
D33, 
D34, 
D35 
D36 
D37, 
D38, 
D39 
D40, 
D41 
D42 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical/ 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspiration/biopsyc,d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood hematologye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunophenotyping (blood and 
bone marrow)f  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Extramedullary leukemic 
localizationsg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xv 
Minimal residual diseaseh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS, Body Weight, Height 
(only baseline) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xv 
Physical examinationi 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xv 
Vital signsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistryl 
X 
X 
X 
X 
Xm 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Xv 
Serum or urine pregnancy testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Evaluation a 
Screening 
Treatment Cycle 1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
D-14 to 
D-1 
D1b D2, D3 
D4 
D5, 
D6, D7 
D8 
D9 
D10, 
D11 
D12, 
D13, 
D14 
D15 
D16, 
D17, 
D18 
D19, 
D20, 
D21 
D22 
D23, 
D24, 
D25 
D26, 
D27, 
D28 
D29 
D30, 
D31, 
D32 
D33, 
D34, 
D35 
D36 
D37, 
D38, 
D39 
D40, 
D41 
D42 
Urinalysiso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetic/FISH  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
Anti-drug antibodies 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
Cytokinesp  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
CRP/ferritinq  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
SAR440234 administrationr 
 
D1b 
 
D4m 
 
D8 
 
 
 
D15 
 
 
D22 
 
 
D29 
 
 
D36 
 
 
 
Hospitalizations 
 
X 
X 
X 
Xm 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
AE assessmentt  
X 
Continuous 
Prior/concomitant medicationu  
X 
Continuous 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a Evaluation: Any specific procedures should be performed after informed consent is signed. The informed consent can be signed >14 days prior to the first administration of SAR440234. Assessments should be 
performed prior to administration of SAR440234 unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. 
b Day 1: Cycle 1 Day 1 refers to the day the patient receives the initial dose of SAR440234.  
c Bone marrow biopsy must be performed at baseline.  
d Bone marrow aspiration will be performed at baseline for morphology (% of blasts) and immunophenotyping, and on Day 42 (±2 days) for evaluation of disease status (morphology, immunophenotyping). 
Additional bone marrow aspirate shall be performed as clinically indicated, or if any of the following occurs: decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile neutropenia Grade 3 and 
Grade 4, or anemia Grade 4 occurs with onset in >14 days before or after Day 42. 
e Blood hematology: Must be performed daily during Cycle 1. Hemoglobin, hematocrit, white blood cell count with differential, percentage of blasts, platelet count. 
f 
Immunophenotyping of the peripheral blood and bone marrow is required at baseline and on Day 42 (±2 days) (to assess CD123- expression and to monitor T-cell subpopulations and activation status). 
g Extramedullary leukemic localizations at physical examination: Evaluation for hepatomegaly, splenomegaly, lymphadenopathy, dermal involvement, gingival infiltration, as clinically indicated, and any other 
examinations as clinically indicated to be performed to assess disease status at baseline. 
h MRD assessment: The modalities of MRD evaluation should be identified and a baseline level of disease involvement should be determined from the Screening bone marrow aspirate. MRD evaluation will be 
performed on the bone marrow if the patient enters CR or CRi. If MRD is positive, the MRD assessment will be repeated on subsequent bone marrow evaluations, or as clinically indicated. 
i 
Physical examination: Examination of major body systems, including cardiovascular, respiratory, neurologic, and digestive.  
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j 
Vital signs: Temperature, blood pressure, heart rate, respiration rate, and oxygen saturation 5 minutes before starting infusion, 0.5 hours after the start of infusion, at the end of infusion, 1 hour, 2 hours, and 
4 hours post-infusion, then daily. During infusion, vital signs must be monitored as follows: temperature, blood pressure, heart rate, oxygen saturation, and respiratory rate every 30 minutes. For each patient 
treated, the hospital must have an available bed in the ICU in case the patient develops hemodynamic or respiratory compromise. The ICU should be staffed by a critical care physician who has experience in 
treating cytokine release syndrome. In addition, the ICU must have the necessary equipment to commence immediate treatment and monitoring of a patient with CRS Grade ≥2 before he/she is admitted to ICU. 
Vital signs monitoring shall be made continuously if CRS Grade ≥2 develops. Specific guidance on monitoring of vital signs during CRS are provided in Section 6.7. 
k Coagulation: Must be performed daily during Cycle 1. PT/INR, aPTT, fibrinogen (and D-dimer at Screening). 
l 
Blood chemistry: Liver tests: SGOT (AST), SGPT (ALT), GGT, total bilirubin, direct bilirubin, AP. Renal function tests and electrolytes: Sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, BUN, 
creatinine, and estimated creatinine clearance (Cockcroft-Gault formula), uric acid. Others: LDH, albumin, and total protein. Serology at screening: testing for active hepatitis B virus, and hepatitis C virus infection. 
Patients should be monitored every 8 hours after the start of drug administration and for at least 72 hours after the end of infusion for signs and symptoms of tumor lysis: serum creatinine, potassium, calcium, 
magnesium, phosphorus, and uric acid. Blood chemistry will also be rechecked 8 hours or less prior to each administration of SAR440234. 
m Additional assessments/Administration of SAR440234/Hospitalization: Only for patients treated in Dose Level ≥3. 
n Serum or urine pregnancy test: Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to the initial dose of study treatment. 
o Urinalysis: Dipstick for pH, protein, glucose, at baseline, then as clinically indicated and at EOT. 
p Plasma cytokines (including interleukin-6 and interferon-γ): will be collected at the time points specified in the pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An additional 
sample will be taken at onset of CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
q CRP/ferritin: will be collected at the same time points as cytokines. 
r 
SAR440234 administration: Systematic prophylactic premedication with dexamethasone 20 mg IV 4 and 1 hour prior to infusion of SAR440234 and montelukast 10 mg oral (PO) 4 hours prior to infusion are 
required. Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has occurred in a previous patient or previous administration in the same patient. Specific instructions for the 
preparation and administration of SAR440234 are provided in the Pharmacy Manual. 
s Hospitalization: Patients will be hospitalized for the duration of the SAR440234 infusion (1 to 19 hours), and for 72 hours after completion of each subsequent infusion. For DL ≥3, patients will be hospitalized 
continuously from Day 1 of Week 1 until 72 hours after completion of the third infusion, ie, for 11 days. 
t 
Adverse event assessment: The period of observation for collection of adverse events extends from the signature of the ICF until 30 days after the last administration of the SAR440234. Serious adverse events, 
AESIs, pregnancy, and overdose reports should be assessed and reported as described in the protocol. SAEs and ongoing treatment-related AEs should be followed beyond EOT until resolution or stabilization. 
u Concomitant medication assessment: The period of collection of concomitant medications extends from the signature of the ICF until EOT, and post EOT if associated with ongoing SAEs or ongoing treatment-
related AEs. 
v The investigations and test scheduled for Day 42 may be performed on the next day if treatment continues after the current cycle; in this case the tests and investigations must be performed before start of next 
infusion. If the treatment won't be continued after the current cycle, all the planned tests and investigations for Day 42 must be performed on the day that the decision is made that the patient will not continue 
treatment. 
Abbreviations: AE=adverse event, AESI=adverse events of special interest, ALT=alanine aminotransferase, AML=acute myeloid leukemia, ANC=absolute neutrophil count, AP=alkaline phosphatase, aPTT=activated 
partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CD123=cluster of differentiation 123, CR=complete response, CRi=complete response with incomplete count recovery, 
CRP=C-reactive protein, D=day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group performance status, FISH=fluorescent in situ hybridization, GGT=gamma glutamyl transferase, 
ICF=informed consent form, ICU=intensive care unit, INR=international normalized ratio, LDH=lactate dehydrogenase, MRD=minimal residual disease, PO=oral, PT=prothrombin time, SAE=serious adverse event, 
SGOT=serum glutamate-oxalate transferase, SGPT=serum glutamate-pyruvate transferase. 
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1.2.2 Dose Escalation Part: Treatment Cycle 2 and Subsequent, End of Treatment, and Follow-up  
Evaluation a 
Treatment Cycle 2 and Subsequent 
EOTb 
FUc 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
 
 
D1d 
D2, D3, 
D4 
D5, D6, 
D7 
D8 
D9, D10, 
D11 
D15 
D16, 
D17, D18 
D22 
D23, 
D24, D25 
D29 
D30, 
D31, D32 
D36 
D37, 
D38, D39 
D42 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiratione  
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Blood hematologyg  
X 
Xf 
Xf 
X 
 
X 
 
X 
 
X 
 
X 
 
Xw 
X 
 
Immunophenotyping (blood 
and bone marrow)h  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Extramedullary leukemic 
localizationsi  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xw 
X 
 
Minimal residual diseasej  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS, Body Weight 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xw 
X 
 
Physical examinationk 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xw 
X 
 
Vital signsl  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xw 
X 
 
Other laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationm  
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Xw 
X 
 
Blood chemistryn  
X 
Xf 
 
X 
Xf 
X 
 
X 
 
X 
 
X 
 
Xw 
X 
 
Serum or urine pregnancy 
testo  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysisp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetics 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
Anti-drug antibodies 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
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Evaluation a 
Treatment Cycle 2 and Subsequent 
EOTb 
FUc 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
 
 
D1d 
D2, D3, 
D4 
D5, D6, 
D7 
D8 
D9, D10, 
D11 
D15 
D16, 
D17, D18 
D22 
D23, 
D24, D25 
D29 
D30, 
D31, D32 
D36 
D37, 
D38, D39 
D42 
 
 
Cytokinesq  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
CRP/ferritinr  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
SAR440234 
administrations 
D1 
 
 
D8 
 
D15 
 
D22 
 
D29 
 
D36 
 
 
 
 
Hospitalizationt 
X 
Xf 
 
X 
Xf 
X 
 
X 
 
X 
 
X 
 
 
 
 
AE assessmentu  
Continuous 
X 
 
Concomitant medicationv  
Continuous 
 
 
Disease statusw 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
a Evaluation: Assessments should be performed prior to administration of SAR440234 (end of the previous cycle) unless otherwise indicated, at the end of the patient’s participation in the trial, and at follow-up. 
Results should be reviewed by the Investigator prior to the administration of the next dose. 
b End of treatment (within 30 days after the last administration of SAR440234): Obtain end of treatment assessments. If the patient does not plan to return for an EOT visit, the EOT evaluation must be 
performed on the day that the decision is made that the patient will discontinue SAR440234. 
c Post-study follow-up for disease status, IMP-related AEs, and SAEs: Patients without documented disease progression at the end of a treatment visit who have not yet started treatment with another anti-cancer 
therapy will proceed with monthly follow-up visits until initiation of another anti-cancer therapy, disease progression, study cut-off date, or death. If the patient is unable to attend monthly study visits, the investigator 
must obtain study follow up information via telephone call and record review from the patient’s treating physicians. 
d Day 1: Cycles run consecutively so that Day 1 of each cycle is normally 7 days after the start of the last infusion in the previous cycle. 
e Bone marrow aspiration will be performed for morphology (% of blasts) on Day 42 (±2 days) of Cycle 2 for evaluation of disease status. Subsequent bone marrow aspirates will be performed when clinically 
indicated, or if any of the following occurs: decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile neutropenia Grade 3 and Grade 4, anemia Grade 4 occurs with onset in >14 days before 
or after Day 42. 
f 
Cycle 2 assessments: Not required during Cycle 3 and subsequent cycles, unless clinically indicated. If the patient discontinues SAR440234 prior to the end of cycle 2, the day 42 assessments must be 
performed on the day that the decision is made that the patient will not continue SAR440234.  
g Blood hematology: Daily during Week 1 of Cycle 2, then weekly thereafter (on IMP administration days and on Day 42). Hemoglobin, hematocrit, white blood cell count with differential, percentage of blasts, 
platelet count. If the patient discontinues SAR440234 prior to the end of cycle 2, the day 42 assessments must be performed on the day that the decision is made that the patient will not continue SAR440234. 
h Immunophenotyping of the peripheral blood and bone marrow is required on Day 42 (±2 days) of Cycle 2 (to assess CD123- expression and to monitor T-cell subpopulations and activation status). Bone marrow 
aspiration is not required for immunophenotyping at the end of subsequent cycles and at EOT unless clinically indicated; the test will be done using blood.  
i 
Extramedullary leukemic localizations at physical examination: Evaluation for hepatomegaly, splenomegaly, lymphadenopathy, dermal involvement, gingival infiltration, as clinically indicated. 
j 
MRD assessment: MRD evaluation will be performed on the bone marrow if the patient enters CR or CRi. If MRD is positive, the MRD assessment will be repeated on subsequent bone marrow evaluations, or as 
clinically indicated.  
k Physical examination: Examination of major body systems, including cardiovascular, respiratory, neurologic, and digestive.  
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l 
Vital signs: Temperature, blood pressure, heart rate, respiration rate, and oxygen saturation 5 minutes before starting infusion, at the end of infusion, 1 hour, 2 hours, and 4 hours post-infusion, then as clinically 
indicated at least until 72 hours from the start of the infusion. During infusion, vital signs must be monitored as follows: temperature, blood pressure, heart rate, oxygen saturation, and respiratory rate every 
30 minutes. Specific guidance on monitoring of vital signs during CRS are provided in Section 6.7. 
m Coagulation: PT/INR, aPTT, fibrinogen. 
n Blood chemistry: Liver tests: SGOT (AST), SGPT (ALT), GGT, total bilirubin, direct bilirubin, AP. Renal function tests and electrolytes: Sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, BUN, 
creatinine, and estimated creatinine clearance (Cockcroft-Gault formula), uric acid. Others: LDH, albumin, and total protein. Patients should be monitored every 8 hours after the start of drug administration and for 
at least 72 hours after the end of the Week 1 and Week 2 infusions of Cycle 2 only, for signs and symptoms of tumor lysis: serum creatinine, potassium, calcium, magnesium, phosphorus, and uric acid. Blood 
chemistry will also be rechecked 8 hours or less prior to each administration of SAR440234. 
o Serum or urine pregnancy test: Women of childbearing potential must have a negative serum or urine pregnancy test result at the end of study evaluation (Day 30 of the last cycle). 
p Urinalysis: Dipstick for pH, protein, glucose, at baseline, then as clinically indicated and at EOT. 
q Plasma cytokines (including interleukin-6 and interferon-γ) will be collected at the time points specified in the pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An additional 
sample will be taken at onset of CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
r 
CRP/ferritin: will be collected at the same time points as cytokines. 
s SAR440234 administration: Systematic prophylactic premedication with dexamethasone 20 mg IV 4 and 1 hour prior to infusion of SAR440234 and montelukast 10 mg oral (PO) 4 hours prior to infusion are 
required. Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has occurred in a previous patient or previous administration in the same patient. Specific instructions for the 
preparation and administration of SAR440234 are provided in the Pharmacy Manual. 
t 
Hospitalization: During Cycle 2, patients will be hospitalized for the duration of each of the first 2 SAR440234 infusions (1 to 19 hours), and for 72 hours after completion. If the patient has tolerated the first 
2 infusions during Cycle 2, the patient will be hospitalized only for the duration of each subsequent infusion (1 to 19 hours). During subsequent cycles, patients must be hospitalized only for the duration of infusion. 
u Adverse event assessment: The period of observation for collection of adverse events extends from the signature of the ICF until 30 days after the last administration of SAR440234. Serious adverse events, 
AESIs, pregnancy, and overdose reports should be assessed and reported as described in the protocol. SAEs and ongoing treatment-related AEs should be followed beyond EOT until resolution or stabilization. 
v Concomitant medication assessment: The period of collection of concomitant medications extends from the signature of the ICF until EOT, and post EOT if associated with ongoing SAEs or ongoing 
treatment-related AEs. 
w Disease status: The treating physician will collect monthly the patient’s disease status (CR, CRi, stable disease, relapse, or progressive disease) until the patient dies or starts new anti-neoplastic therapy, to 
collect either the date of progressive disease or the initiation of further antitumor therapy. 
w The investigations and test scheduled for Day 42 may be performed on the next day if treatment continues after the current cycle; in this case the tests and investigations must be performed before start of next 
infusion. If the treatment won't be continued after the current cycle, all the planned tests and investigations for Day 42 must be performed on the day that the decision is made that the patient will not continue 
treatment. 
 
Abbreviations: AE=adverse event, AESI=adverse events of special interest, ALT=alanine aminotransferase, AML=acute myeloid leukemia, ANC=absolute neutrophil count, AP=alkaline phosphatase, aPTT=activated 
partial thromboplastin time, AST=aspartate aminotransferase, B-ALL=B-cell acute lymphoblastic leukemia, BUN=blood urea nitrogen, CD123=cluster of differentiation 123, CR=complete response, CRi=complete 
response with incomplete count recovery, CRP=C-reactive protein, D=day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group performance status, EOT=end of treatment, FU=follow-up, 
GGT=gamma glutamyl transferase, ICF=informed consent form, INR=international normalized ratio, LDH=lactate dehydrogenase, MRD=minimal residual disease, PO=oral, PT=prothrombin time, SAE=serious 
adverse event, SGOT=serum glutamate-oxalate transferase, SGPT=serum glutamate-pyruvate transferase. 
 
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1.2.3 Expansion Part: Screening and Treatment Cycle 1  
 
Evaluationa 
Screen-
ing 
Treatment Cycle 1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
D-14 to 
D-1 
D1b 
D2, 
D3 
D4 
D5, 
D6, D7 
D8 
D9, 
D10, 
D11 
D12, 
D13, 
D14 
D15 
D16, 
D17, 
D18 
D19, 
D20, 
D21 
D22 
D23, 
D24, 
D25 
D26, 
D27, 
D28 
D29 
D30, 
D31, 
D32 
D33, 
D34, 
D35 
D36 
D37, 
D38, 
D39 
D40, 
D41 
D42 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical/ 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspiration/biopsyc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood hematologyd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunophenotyping (blood 
and bone marrow)e  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Extramedullary leukemic 
localizationsf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xx 
Minimal residual diseaseg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS, Body Weight, 
Height (only baseline) 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xx 
Physical examinationh 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xx 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood chemistryk 
X 
X 
X 
X 
Xl 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Xx 
Serum or urine pregnancy 
testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Evaluationa 
Screen-
ing 
Treatment Cycle 1 
 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
D-14 to 
D-1 
D1b 
D2, 
D3 
D4 
D5, 
D6, D7 
D8 
D9, 
D10, 
D11 
D12, 
D13, 
D14 
D15 
D16, 
D17, 
D18 
D19, 
D20, 
D21 
D22 
D23, 
D24, 
D25 
D26, 
D27, 
D28 
D29 
D30, 
D31, 
D32 
D33, 
D34, 
D35 
D36 
D37, 
D38, 
D39 
D40, 
D41 
D42 
Urinalysisn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetic/FISH  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
Anti-drug antibodies 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
Cytokineso  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
CRP/ferritinp  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
SAR440234 
administrationq 
 
D1a 
 
D4l 
 
D8 
 
 
D15 
 
 
D22 
 
 
D29 
 
 
D36 
 
 
 
Hospitalizationr 
 
X 
X 
X 
Xl 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
AE assessments  
X 
Continuous 
Prior/concomitant 
medicationt  
X 
Continuous 
Disease status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a Evaluation: Any specific procedures should be performed after informed consent is signed. The informed consent can be signed >14 days prior to the first administration of SAR440234. Assessments should be 
performed prior to administration of SAR440234 unless otherwise indicated. Results should be reviewed by the Investigator prior to the administration of the next dose. 
b Day 1: Cycle 1 Day 1 refers to the day the patient receives the initial dose of SAR440234.  
c Bone marrow aspiration will be performed at baseline for morphology (% of blasts) and immunophenotyping, and on Day 42 (±2 days). Additional bone marrow aspirate shall be performed as clinically indicated, 
or if any of the following occurs: decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile neutropenia Grade 3 and Grade 4, anemia Grade 4 occurs with onset in >14 days before or after 
Day 42. 
d Blood hematology: Must be performed daily during Cycle 1. Hemoglobin, hematocrit, white blood cell count with differential, percentage of blasts, platelet count. 
e Immunophenotyping of the peripheral blood and bone marrow is required at baseline and on Day 42 (±2 days) (to assess CD123- expression and to monitor T-cell subpopulations and activation status).  
f 
Extramedullary leukemic localizations at physical examination: Evaluation for hepatomegaly, splenomegaly, lymphadenopathy, dermal involvement, gingival infiltration, as clinically indicated, and any other 
examinations as clinically indicated to be performed to assess disease status at baseline. 
g MRD assessment: The modalities of MRD evaluation should be identified and a baseline level of disease involvement should be determined from the Screening bone marrow aspirate. MRD evaluation will be 
performed on the bone marrow if the patient enters CR or CRi. If MRD is positive, the MRD assessment will be repeated on subsequent bone marrow evaluations, or as clinically indicated. 
h Physical examination: Examination of major body systems, including cardiovascular, respiratory, neurologic, and digestive.  
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i 
Vital signs: Temperature, blood pressure, heart rate, respiration rate, and oxygen saturation 5 minutes before starting infusion, 0.5 hours after the start of infusion, at the end of infusion, 1 hour, 2 hours, and 
4 hours post-infusion, then daily. During infusion, vital signs must be monitored as follows: temperature, blood pressure, heart rate, oxygen saturation, and respiratory rate every 30 minutes. For each patient 
treated, the hospital must have an available bed in the ICU in case the patient develops hemodynamic or respiratory compromise. The ICU should be staffed by a critical care physician who has experience in 
treating cytokine release syndrome. In addition, the ICU must have the necessary equipment to commence immediate treatment and monitoring of a patient with CRS Grade ≥2 before he/she is admitted to ICU. 
Vital signs monitoring shall be made continuously if CRS Grade ≥2 develops. Specific guidance on monitoring of vital signs during CRS are provided in Section 6.7. 
j 
Coagulation: Must be performed daily during Cycle 1. PT/INR, aPTT, fibrinogen (and D-dimer at Screening). 
k Blood chemistry: Liver tests: SGOT (AST), SGPT (ALT), GGT, total bilirubin, direct bilirubin, AP. Renal function tests and electrolytes: Sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, BUN, 
creatinine, and estimated creatinine clearance (Cockcroft-Gault formula), uric acid. Others: LDH, albumin, and total protein. Serology at screening: testing for active hepatitis B virus, and hepatitis C virus infection. 
Patients should be monitored every 8 hours after the start of drug administration and for at least 72 hours after the end of infusion for signs and symptoms of tumor lysis: serum creatinine, potassium, calcium, 
magnesium, phosphorus, and uric acid. Blood chemistry will also be rechecked 8 hours or less prior to each administration of SAR440234. 
l 
Additional assessments/Administration of SAR440234/Hospitalization: Only if Dose Level ≥3 is selected for administration in the Expansion Part. 
m Serum or urine pregnancy test: Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to the initial dose of study treatment. 
n Urinalysis: Dipstick for pH, protein, glucose, at baseline, then as clinically indicated. 
o Plasma cytokines (including interleukin-6 and interferon-γ): will be collected at the time points specified in the pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An additional 
sample will be taken at onset of CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
p CRP/ferritin: will be collected at the same time points as cytokines. 
q SAR440234 administration: Systematic prophylactic premedication with dexamethasone 20 mg IV 4 and 1 hour prior to infusion of SAR440234 and montelukast 10 mg oral (PO) 4 hours prior to infusion are 
required. Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has occurred in a previous patient or previous administration in the same patient. Specific instructions for the 
preparation and administration of SAR440234 are provided in the Pharmacy Manual. 
r 
Hospitalization: Patients will be hospitalized for the duration of the SAR440234 infusion (1 to 19 hours), and for 72 hours after completion of each infusion. If the RP2D is DL ≥3, patients will be hospitalized continuously from Day 1 of 
Week 1 until 72 hours after completion of the third infusion, ie, for 11 days. 
s Adverse event assessment: The period of observation for collection of adverse events extends from the signature of the ICF until 30 days after the last administration of SAR440234. Serious adverse events, 
AESIs, pregnancy, and overdose reports should be assessed and reported as described in the protocol. SAEs and ongoing treatment-related AEs should be followed beyond EOT until resolution or stabilization. 
t 
Concomitant medication assessment: The period of collection of concomitant medications extends from the signature of the ICF until EOT, and post EOT if associated with ongoing SAEs or ongoing 
treatment-related AEs. 
x The investigations and test scheduled for Day 42 may be performed on the next day if treatment continues after the current cycle; in this case the tests and investigations must be performed before start of next 
infusion. If the treatment won't be continued after the current cycle, all the planned tests and investigations for Day 42 must be performed on the day that the decision is made that the patient will not continue 
treatment. 
Abbreviations: AE=adverse event, AESI=adverse events of special interest, ALT=alanine aminotransferase, ANC=absolute neutrophil count, AP=alkaline phosphatase, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, CD123=cluster of differentiation 123, CR=complete response, CRi=complete response with incomplete count recovery, CRP=C-reactive protein, 
CRS=cytokine release syndrome, D=day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group performance status, FISH=fluorescent in situ hybridization, GGT=gamma glutamyl transferase, 
ICF=informed consent form, ICU=intensive care unit, INR=international normalized ratio, IV=intravenous, LDH=lactate dehydrogenase, MRD=minimal residual disease, PO=oral, PT=prothrombin time, 
RP2D=recommended Phase 2 dose, SAE=serious adverse event, SGOT=serum glutamate-oxalate transferase, SGPT=serum glutamate-pyruvate transferase. 
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1.2.4 Expansion Part: Treatment Cycle 2 and Subsequent, End of Treatment, and Follow-up  
 
Evaluationa 
Treatment Cycle 2 and Subsequent 
EOTb 
FUc 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
 
 
D1d 
D2, D3, D4 D5, D6, D7 
D8 
D9, D10, 
D11 
D15 
D22 
D29 
D36 
D42 
 
 
Disease assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiratione 
 
 
 
 
 
 
 
 
 
Xf 
 
 
Blood hematologyg  
X 
Xf 
Xf 
X 
 
X 
X 
X 
X 
Xy 
X 
 
Immunophenotyping (blood 
and bone marrow)h 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Extramedullary leukemic 
localizationsi  
X 
 
 
 
 
 
 
 
 
Xf,y 
X 
 
Minimal residual diseasej  
 
 
 
 
 
 
 
 
 
X 
X 
 
Other clinical assessments 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS, Body Weight 
X 
 
 
X 
 
X 
X 
X 
X 
Xy 
X 
 
Physical examinationk 
X 
 
 
X 
 
X 
X 
X 
X 
Xy 
X 
 
Vital signsl  
X 
Xf 
 
X 
Xf 
X 
X 
X 
X 
Xy 
X 
 
Other laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulationm  
X 
 
 
X 
 
X 
X 
X 
X 
Xy 
X 
 
Blood chemistryn  
X 
Xf 
 
X 
Xf 
X 
X 
X 
X 
Xy 
X 
 
Serum or urine pregnancy 
testo  
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysisp 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetics 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
 
 
Anti-drug antibodies 
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
 
 
Cytokinesq  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
 
 
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Evaluationa 
Treatment Cycle 2 and Subsequent 
EOTb 
FUc 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
 
 
 
D1d 
D2, D3, D4 D5, D6, D7 
D8 
D9, D10, 
D11 
D15 
D22 
D29 
D36 
D42 
 
 
CRP/ferritinr  
See Pharmacokinetics/Pharmacodynamics Flow-Charts 
 
 
SAR440234 
administrations 
D1 
 
 
D8 
 
D15 
D22 
D29 
D36 
 
 
 
Hospitalizationt 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
AE assessmentu 
Continuous 
X 
 
Concomitant medicationv 
Continuous 
 
 
Disease statusw 
 
 
 
 
 
 
 
 
 
X 
X 
X 
a Evaluation: Assessments should be performed prior to administration of SAR440234 (end of the previous cycle) unless otherwise indicated, at the end of the patient’s participation in the trial, and at follow-up. 
Results should be reviewed by the Investigator prior to the administration of the next dose. If the patient is unable to attend monthly study visits, the investigator must obtain study follow up information via 
telephone call and record review from the patient’s treating physicians. 
b End of treatment (within 30 days after the last administration of SAR440234): Obtain end of treatment assessments. If the patient does not plan to return for an EOT visit, the EOT evaluation must be 
performed on the day that the decision is made that the patient will not continue SAR440234. 
c Post-study follow-up for disease status, IMP-related AEs, and SAEs: Patients without documented disease progression at the end of a treatment visit who have not yet started treatment with another anti-cancer 
therapy will proceed with monthly follow-up visits until initiation of another anti-cancer therapy, disease progression, study cut-off date, or death.  If the patient is unable to attend monthly study visits, the 
investigator must obtain study follow up information via telephone call and record review from the patient’s treating physicians. 
d Day 1: Cycles run consecutively so that Day 1 of each cycle is normally 7 days after the start of the last infusion in the previous cycle. 
e Bone marrow aspiration will be performed for morphology (% of blasts) on Day 42 (±2 days) of Cycle 2 for evaluation of disease status. Subsequent bone marrow aspirates will be performed when clinically 
indicated, or if any of the following occurs: decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile neutropenia Grade 3 and Grade 4, anemia Grade 4 occurs with onset in >14 days before 
or after Day 42.  
f 
Flagged assessments: Cycle 2 only. Not required during Cycle 3 and subsequent cycles unless clinically indicated. 
g Blood hematology: Daily during Week 1 of Cycle 2, then weekly thereafter (on IMP administration days and on Day 42). Hemoglobin, hematocrit, white blood cell count with differential, percentage of blasts, 
platelet count. 
h Immunophenotyping of the peripheral blood and bone marrow is required on Day 42 (±2 days) of Cycle 2 (to assess CD123- expression and to monitor T-cell subpopulations and activation status). Bone marrow 
aspiration is not required for immunophenotyping at the end of subsequent cycles and at EOT unless clinically indicated.; the test will be done using blood.  
i 
Extramedullary leukemic localizations at physical examination: Evaluation for hepatomegaly, splenomegaly, lymphadenopathy, dermal involvement, gingival infiltration, as clinically indicated.  
j 
MRD assessment: MRD evaluation will be performed on the bone marrow if the patient enters CR or CRi. If MRD is positive, the MRD assessment will be repeated on subsequent bone marrow evaluations, or as 
clinically indicated. 
k Physical examination: Examination of major body systems, including cardiovascular, respiratory, neurologic, and digestive.  
l 
Vital signs: Temperature, blood pressure, heart rate, respiration rate, and oxygen saturation 5 minutes before starting infusion, at the end of infusion, 1 hour, 2 hours, and 4 hours post-infusion, then as clinically 
indicated at least until 72 hours from the start of the infusion. During infusion, vital signs must be monitored as follows: temperature, blood pressure, heart rate, oxygen saturation, and respiratory rate every 
30 minutes. Specific guidance on monitoring of vital signs during CRS are provided in Section 6.7. 
m Coagulation: PT/INR, aPTT, fibrinogen. 
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n Blood chemistry: Liver tests: SGOT (AST), SGPT (ALT), GGT, total bilirubin, direct bilirubin, AP. Renal function tests and electrolytes: Sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, BUN, 
creatinine, and estimated creatinine clearance (Cockcroft-Gault formula), uric acid. Others: LDH, albumin, and total protein. Patients should be monitored every 8 hours after the start of drug administration and for 
at least 72 hours after the end of infusion for signs and symptoms of tumor lysis: serum creatinine, potassium, calcium, magnesium, phosphorus, and uric acid. Blood chemistry will also be rechecked 8 hours or 
less prior to each administration of SAR440234. 
o Serum or urine pregnancy test: Women of childbearing potential must have a negative serum or urine pregnancy test result at the end of study evaluation (Day 30 of the last cycle). 
p Urinalysis: Dipstick for pH, protein, glucose, at baseline, then as clinically indicated and at EOT. 
q Plasma cytokines (including interleukin-6 and interferon-γ): will be collected at the time points specified in the pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An additional 
sample will be taken at onset of CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
r 
Serum CRP/ferritin: will be collected at the same time points as cytokines. 
s SAR440234 administration: Systematic prophylactic premedication with dexamethasone 20 mg IV 4 and 1 hour prior to infusion of SAR440234 and montelukast 10 mg oral (PO) 4 hours prior to infusion are 
required. Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has occurred in a previous patient or previous administration in the same patient. Specific instructions for the 
preparation and administration of SAR440234 are provided in the Pharmacy Manual. 
t 
Hospitalization: During Cycle 2, if the patient has tolerated the SAR440234 infusion during Cycle 1, the patient will be hospitalized only for the duration of each subsequent infusion (1 to 19 hours).  
u Adverse event assessment: The period of observation for collection of adverse events extends from the signature of the ICF until 30 days after the last administration of SAR440234. Serious adverse events, 
AESIs, pregnancy, and overdose reports should be assessed and reported as described in the protocol. Serious adverse events and ongoing treatment-related adverse events should be followed beyond EOT until 
resolution or stabilization. 
v Concomitant medication assessment: The period of collection of concomitant medications extends from the signature of the ICF until EOT, and post EOT if associated with ongoing SAEs or ongoing treatment-
related AEs. 
w Disease status: The treating physician will collect monthly the patient’s disease status (CR, CRi, stable disease, relapse, or progressive disease) until the patient dies or starts new anti-neoplastic therapy, to 
collect either the date of progressive disease or the initiation of further antitumor therapy. 
y The investigations and test scheduled for Day 42 may be performed on the next day if treatment continues after the current cycle; in this case the tests and investigations must be performed before start of next 
infusion. If the treatment won't be continued after the current cycle, all the planned tests and investigations for Day 42 must be performed on the day that the decision is made that the patient will not continue 
treatment. 
Abbreviations: AE=adverse event, AESI=adverse events of special interest, ALT=alanine aminotransferase, ANC=absolute neutrophil count, AP=alkaline phosphatase, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, CD123=cluster of differentiation 123, CR=complete response, CRi=complete response with incomplete count recovery, CRP=C-reactive protein, D=day, 
ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group performance status, EOT=end of treatment, FU=follow-up, GGT=gamma glutamyl transferase, ICF=informed consent form, 
INR=international normalized ratio, LDH=lactate dehydrogenase, MRD=minimal residual disease, PO=oral, PT=prothrombin time, SAE=serious adverse event, SGOT=serum glutamate-oxalate transferase, 
SGPT=serum glutamate-pyruvate transferase. 
 
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1.3 
PHARMACOKINETIC, PHARMACODYNAMIC, BIOMARKER AND IMMUNOGENICITY FLOW CHARTS  
1.3.1 Cycle 1: Week 1  
 
 
Screening 
Cycle 1 
Week within Cycle 
Week 1 
Day within Cycle 
D-14 to  
D-1 
Day 1 
Day 4 (Week 1 Dose Levels ≥3 only) 
Time (decimal hours) 
  
SOI 
EOI 
EOI  
+1h 
EOI  
+2h 
EOI  
+5h 
EOI 
+7h 
EOI 
 +24h 
EOI 
 +48h 
72ha, e  
SOI 
EOI 
EOI  
+2h 
EOI  
+5h 
EOI 
 +24h 
Indicative clock time 
(based on a 2h 
infusion) 
8:00 
AM 
8:00 
AM 
10:00 
AM 
11:00 
AM 
12:00 
PM 
3:00 
PM 
5:00 
PM 
10:00 
AM 
10:00 
AM 
8:00 
AM 
8:00 
AM 
10:00 
AM 
12:00 
AM 
3:00 
PM 
10:00 
AM 
Treatment (IV infusion) 
SAR440234 
 
X-------------------X 
 
 
 
 
 
 
 
X-------------------X 
 
 
 
Pharmacokinetics 
SAR440234b, c, d 
 
P00e 
P01f 
P02 
P03 
P04 
P05 
P06 
P07 
P08a, e 
 
P09f, g 
P10g 
P11g 
P12g 
Immunogenicity 
ADAb, c, d 
 
AB00e 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers 
Cytokinesb, c, i, j 
CS00 
C00e 
C01f 
C02 
C03 
C04 
C05 
C06 
C07 
C08a, e 
 
C09f,g 
C10g 
C11g 
C12g 
a Sample to be drawn immediately before starting the next infusion if the patient is continuing to be treated in the study and there is no dose delay. 
b Refer to laboratory manual for sample collection, processing, and shipping. 
c The sampling time-points for PK, ADA and cytokines may be modified during the course of the study (ie, omitting samples) based on the updated knowledge of SAR440234 behavior. 
d Sampling for PK analysis and ADA detection will be stopped in all patients at the second study cut-off date. 
e Pre-dose samples to be collected strictly before start of SAR440234 infusion. 
f 
End of infusion sample to be collected within 10 minutes before the actual end of infusion. 
g Samples to be collected from Dose Level 3. 
h Mid of infusion sample to be collected during SAR440234 infusion only for infusion length ≥5 hours. 
i 
An additional sample (CA00, CA01...) must be collected in case of Grade ≥2 CRS if it occurs, or as soon as it is diagnosed. 
j 
CRP/ferritin will be measured at the same times as cytokines. 
 
Abbreviations: AB=antibody, ADA=anti-drug antibody (ie, anti-SAR440234 antibody), C=cytokines, CRS=cytokine release syndrome, CS=cytokines screening, EOI=end of infusion, h=hours, IV=intravenous, 
P=plasma, PK=pharmacokinetic, SOI=start of infusion 
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1.3.2 Cycle 1: Week 2 and Week 3  
 
 
Cycle 1 Continued 
Week within Cycle 
Week 2 
Week 3 
Day within Cycle 
Day 8 
Day 15 
Time (decimal hours) 
SOI 
MOI 
EOI 
EOI  
+2h 
EOI 
+5h 
EOI 
+24h 
EOI 
+48h 
72h 
168ha, e 
SOI 
MOI 
EOI 
EOI  
+2h 
EOI  
+5h 
EOI 
 +24h 
Indicative clock time 
(based on a 2h 
infusion) 
8:00 
AM 
9:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
10:00 
AM 
10:00 
AM 
8:00 
AM 
8:00 
AM 
8:00 
AM 
9:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
10:00 
AM 
Treatment (IV infusion) 
SAR440234 
X------------------------------------X 
 
 
 
 
 
 
X------------------------------------X 
 
 
 
Pharmacokinetics 
SAR440234b, c, d 
P13a, e 
P14h 
P15f 
P16 
P17 
 
 
 
P18a, e 
 
P19h 
P20f 
P21 
P22 
P23 
Immunogenicity 
ADAb, c, d  
AB01e 
 
 
 
 
 
 
 
AB02e 
 
 
 
 
 
 
Biomarkers 
Cytokinesb, c, i ,j  
C13a, e 
C14h 
C15f 
C16 
C17 
C18 
C19 
C20 
C21a, e 
 
C22h 
C23f 
C24 
C25 
C26 
a Sample to be drawn immediately before starting the next infusion if the patient is continuing to be treated in the study and there is no dose delay. 
b Refer to laboratory manual for sample collection, processing, and shipping. 
c The sampling time-points for PK, ADA and cytokines may be modified during the course of the study (ie, omitting samples) based on the updated knowledge of SAR440234 behavior. 
d Sampling for PK analysis and ADA detection will be stopped in all patients at the second study cut-off date. 
e Pre-dose samples to be collected strictly before start of SAR440234 infusion. 
f 
End of infusion sample to be collected within 10 minutes before the actual end of infusion. 
g Samples to be collected from Dose Level 3. 
h Mid of infusion sample to be collected during SAR440234 infusion only for infusion length ≥5 hours. 
i 
An additional sample (CA00, CA01...) must be collected in case of Grade ≥2 CRS if it occurs, or as soon as it is diagnosed. 
j 
CRP/ferritin will be measured at the same times as cytokines. 
 
Abbreviations: AB=antibody, ADA=anti-drug antibody (ie, anti-SAR440234 antibody), C=cytokines, CRS=cytokine release syndrome, CS=cytokines screening, EOI=end of infusion, h=hours, IV=intravenous, MOI=mid 
of infusion; P=plasma, PK=pharmacokinetic, SOI=start of infusion 
 
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1.3.3 Cycle 1: Weeks 4, Week 5, and Week 6  
 
 
Cycle 1 continued 
Week within Cycle 
Week 4 
Week 5 
Week 6 
Day within Cycle 
Day 22 
Day 29 
Day 36 
Time (decimal hours) 
SOI 
MOI 
EOI 
EOI 
+2h 
EOI  
+5h 
EOI 
+24h 
EOI 
+48h 
72h 
96h 
168ha, e 
SOI 
EOI 
EOI 
+2h 
EOI 
+5h 
SOI 
EOI 
EOI 
+2h 
EOI 
+5h 
Indicative clock time 
(based on a 2h 
infusion) 
8:00 
AM 
9:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
10:00 
AM 
10:00 
AM 
8:00 
AM 
8:00 
AM 
8:00 AM 
8:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
8:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
Treatment (IV infusion) 
SAR440234 
X------------------------------X 
 
 
 
 
 
 
 
X---------------X 
 
 
X---------------X 
 
 
Pharmacokinetics 
SAR440234b, c, d 
P24e 
P25h 
P26f 
P27  
P28 
P29 
P30 
P31 
P32 
P33a, e 
 
P34f 
P35 
 
P36e 
P37f 
P38 
 
Immunogenicity 
ADAb, c, d 
AB03e 
 
 
 
 
 
 
 
 
AB04a,e 
 
 
 
 
 
 
 
 
Biomarkers 
Cytokinesb, c, i, j 
C27e 
C28h 
C29f 
C30 
C31 
C32 
C33 
C34 
 
C35a, e 
 
C36f 
C37 
C38 
C39e 
C40f 
C41 
C42 
a Sample to be drawn immediately before starting the next infusion if the patient is continuing to be treated in the study and there is no dose delay. 
b Refer to laboratory manual for sample collection, processing, and shipping. 
c The sampling time-points for PK, ADA and cytokines may be modified during the course of the study (ie, omitting samples) based on the updated knowledge of SAR440234 behavior. 
d Sampling for PK analysis and ADA detection will be stopped in all patients at the second study cut-off date. 
e Pre-dose samples to be collected strictly before start of SAR440234 infusion. 
f 
End of infusion sample to be collected within 10 minutes before the actual end of infusion. 
g Samples to be collected from Dose Level 3. 
h Mid of infusion sample to be collected during SAR440234 infusion only for infusion length ≥5 hours. 
i 
An additional sample (CA00, CA01...) must be collected in case of Grade ≥2 CRS if it occurs, or as soon as it is diagnosed. 
j 
CRP/ferritin will be measured at the same times as cytokines. 
 
Abbreviations: AB=antibody, ADA=anti-drug antibody (ie, anti-SAR440234 antibody), C=cytokines, CRS=cytokine release syndrome, CS=cytokines screening, D=day, EOI=end of infusion, h=hours, IV=intravenous, 
MOI=mid of infusion; P=plasma, PK=pharmacokinetic, SOI=start of infusion 
 
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1.3.4 Cycle 2 and Subsequent Cycles  
 
Cycle 
Cycle 2 
Subsequent cycles 
End of 
Treatment 
Week within Cycle 
Week 1 
Week 3 
Week 5 
Week 1 
Day within Cycle 
Day 1 
Day 15 
Day 29 
Day 1 
(EOT)
 i 
Time (decimal hours) 
SOI 
MOI 
EOI 
EOI 
+2h 
EOI 
+5h 
SOI 
EOI 
SOI 
EOI 
SOI 
EOI 
EOI 
+2h 
  
Indicative clock time 
(based on a 2h infusion) 
8:00 
AM 
9:00 
AM 
10:00 
AM 
12:00 
PM 
3:00 
PM 
8:00 
AM 
10:00 
AM 
8:00 
AM 
10:00 
AM 
8:00 
AM 
10:00 
AM 
12:00 
PM 
8:00 
AM 
Treatment (IV infusion) 
SAR440234 
X----------------------------X 
  
X----------------------X  
X-----------------X 
X------------------X 
  
Pharmacokinetics 
SAR440234a, b, c 
P00d 
P01e 
P02f 
P03 
  
P04d 
 
P05d 
 
P00d 
P01f 
P02 
  
Immunogenicity 
ADAa, b, c 
AB00d 
  
  
  
  
AB01d 
 
  
AB02d 
 
 
AB00d 
  
  
ABF00 
Biomarkers 
Cytokinesa, b, g, h 
C00d 
C01e 
C02f 
C03 
C04 
  
  
  
  
  
  
  
  
  
  
a Refer to laboratory manual for sample collection, processing, and shipping. 
b The sampling time-points for PK, ADA and cytokines may be modified during the course of the study (ie, omitting samples) based on the updated knowledge of SAR440234 behavior.  
c Sampling for PK analysis and ADA detection will be stopped in all patients at the second study cut-off date. 
d Pre-dose samples to be collected strictly before start of SAR440234 infusion. 
e Mid of infusion sample to be collected during SAR440234 infusion only for infusion length ≥5 hours. 
f 
End of infusion sample to be collected within 10 minutes the actual end of infusion.  
g An additional sample (CA00, CA01...) must be collected in case of Grade ≥2 CRS if it occurs, or as soon as it is diagnosed. 
h CRP/ferritin will be measured at the same times as cytokines. 
i 
EOT evaluation must be performed within 30 days of the last administration of SAR440234. If a patient does not plan to return for an EOT visit, EOT evaluation must be performed on the day that the decision is 
made to discontinue SAR440234. 
 
Abbreviations: AB=antibody, ADA=anti-drug antibody (ie, anti-SAR440234 antibody), C=cytokines, CRP=C-reactive protein, CA=additional cytokines sample, CRS=cytokine release syndrome, CS=cytokines 
screening, EOI=end of infusion, EOT=end of treatment, h=hours, IV=intravenous, MOI=mid of infusion; P=plasma, SOI=start of infusion 
 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
1 
FLOW CHARTS ............................................................................................................................. 15 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 15 
1.2 
STUDY FLOW CHARTS ................................................................................................................ 16 
1.2.1 
Dose Escalation Part: Screening and Treatment Cycle 1 ............................................................. 16 
1.2.2 
Dose Escalation Part: Treatment Cycle 2 and Subsequent, End of Treatment, and Follow-
up ................................................................................................................................................... 19 
1.2.3 
Expansion Part: Screening and Treatment Cycle 1 ....................................................................... 22 
1.2.4 
Expansion Part: Treatment Cycle 2 and Subsequent, End of Treatment, and Follow-up ............. 25 
1.3 
PHARMACOKINETIC, PHARMACODYNAMIC, BIOMARKER AND IMMUNOGENICITY 
FLOW CHARTS ............................................................................................................................. 28 
1.3.1 
Cycle 1: Week 1 ............................................................................................................................. 28 
1.3.2 
Cycle 1: Week 2 and Week 3 ......................................................................................................... 29 
1.3.3 
Cycle 1: Weeks 4, Week 5, and Week 6........................................................................................ 30 
1.3.4 
Cycle 2 and Subsequent Cycles .................................................................................................... 31 
2 
TABLE OF CONTENTS ................................................................................................................ 32 
2.1 
LIST OF TABLES ........................................................................................................................... 39 
2.2 
LIST OF FIGURES ......................................................................................................................... 39 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 40 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 42 
4.1 
INTRODUCTION ............................................................................................................................ 42 
4.2 
SAR440234 .................................................................................................................................... 43 
4.3 
NONCLINICAL TOXICOLOGY ...................................................................................................... 45 
4.4 
PHARMACOKINETICS IN ANIMAL ............................................................................................... 46 
4.5 
STUDY DESIGN RATIONALE ....................................................................................................... 47 
4.5.1 
Choice of starting dose .................................................................................................................. 47 
4.5.2 
Clinical rationale ............................................................................................................................. 48 
4.5.3 
SAR440234 dose and regimen ...................................................................................................... 48 
4.5.4 
Cytokine release syndrome ........................................................................................................... 49 
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4.6 
BENEFIT RISK ASSESSMENT ..................................................................................................... 50 
5 
STUDY OBJECTIVES ................................................................................................................... 52 
5.1 
PRIMARY OBJECTIVES: .............................................................................................................. 52 
5.2 
SECONDARY OBJECTIVES: ........................................................................................................ 52 
5.3 
EXPLORATORY OBJECTIVES: .................................................................................................... 52 
6 
STUDY DESIGN ............................................................................................................................ 53 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 53 
6.2 
STARTING DOSE AND DOSE ESCALATION PART ................................................................... 53 
6.2.1 
Starting dose and dose levels ........................................................................................................ 53 
6.2.2 
Dose-limiting toxicity ...................................................................................................................... 56 
6.3 
MAXIMUM ADMINISTERED DOSE / MAXIMUM TOLERATED DOSE ........................................ 57 
6.4 
RETREATMENT OF PATIENTS ................................................................................................... 58 
6.5 
DOSE DELAYS/MODIFICATIONS ................................................................................................ 58 
6.5.1 
Dose delays ................................................................................................................................... 58 
6.5.2 
Dose modifications ......................................................................................................................... 58 
6.5.3 
Dose delay/modification for cytokine release syndrome and infusion-related reactions ............... 60 
6.5.4 
Dose delay/modification for hematological adverse events due to SAR440234 ........................... 62 
6.5.5 
Dose delay/modification for other adverse events not including hematological adverse 
events or cytokine release syndrome due to SAR440234 ............................................................. 63 
6.6 
EXPANSION COHORT TO CONFIRM THE MTD ........................................................................ 65 
6.7 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS ...................................................... 66 
6.7.1 
Recommendations for management of Cytokine Release Syndrome ........................................... 66 
6.7.2 
Tumor Lysis Syndrome (TLS) ........................................................................................................ 68 
6.7.3 
Hematological adverse events ....................................................................................................... 68 
6.7.4 
Other adverse events ..................................................................................................................... 68 
6.7.5 
Initiation of a new cycle of therapy ................................................................................................. 68 
6.8 
DURATION OF STUDY PARTICIPATION .................................................................................... 69 
6.8.1 
Duration of study participation for each patient ............................................................................. 69 
6.8.2 
Determination of end of clinical trial (all patients) .......................................................................... 70 
6.9 
INTERIM ANALYSIS ...................................................................................................................... 70 
6.10 
STUDY COMMITTEES .................................................................................................................. 70 
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7 
SELECTION OF PATIENTS .......................................................................................................... 71 
7.1 
NUMBER OF PATIENTS ............................................................................................................... 71 
7.2 
INCLUSION CRITERIA .................................................................................................................. 71 
7.3 
EXCLUSION CRITERIA ................................................................................................................ 72 
8 
STUDY TREATMENTS ................................................................................................................. 74 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................... 74 
8.1.1 
Dose of drug per administration ..................................................................................................... 74 
8.1.2 
Preparation, reconstitution, and administration of SAR440234 ..................................................... 74 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 74 
8.3 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 75 
8.4 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 75 
8.5 
RESPONSIBILITIES ...................................................................................................................... 76 
8.5.1 
Treatment accountability and compliance...................................................................................... 76 
8.5.2 
Return and/or destruction of treatments ........................................................................................ 76 
8.6 
CONCOMITANT TREATMENT ..................................................................................................... 77 
8.7 
POST INVESTIGATIONAL MEDICINAL PRODUCT .................................................................... 77 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 78 
9.1 
SAFETY ......................................................................................................................................... 78 
9.1.1 
Dose-limiting toxicities.................................................................................................................... 78 
9.1.2 
Adverse events .............................................................................................................................. 79 
9.1.3 
Laboratory safety variables ............................................................................................................ 79 
9.1.4 
Clinical examinations ..................................................................................................................... 80 
9.1.5 
Immunogenicity .............................................................................................................................. 80 
9.1.5.1 
Sampling times ............................................................................................................................... 80 
9.1.5.2 
Sample handling procedures ......................................................................................................... 80 
9.1.5.3 
Bioanalytical method ...................................................................................................................... 80 
9.1.6 
Other safety endpoints ................................................................................................................... 80 
9.2 
PHARMACOKINETIC EVALUATION ............................................................................................ 81 
9.2.1 
Sampling times ............................................................................................................................... 81 
9.2.2 
Pharmacokinetic sample handling procedure ................................................................................ 81 
9.2.3 
Bioanalytical method ...................................................................................................................... 81 
9.2.4 
Pharmacokinetic parameters ......................................................................................................... 81 
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9.3 
PHARMACOGENETIC ASSESSMENT ......................................................................................... 82 
9.4 
SPECIFIC ASSESSMENTS .......................................................................................................... 82 
9.4.1 
Biomarker assessments ................................................................................................................. 82 
9.4.1.1 
Cytokine and acute phase protein assessment ............................................................................. 83 
9.4.1.2 
Immunophenotyping by flow cytometry ......................................................................................... 83 
9.4.1.3 
Disease molecular subtype ............................................................................................................ 83 
9.4.1.4 
Minimal residual disease ................................................................................................................ 83 
9.5 
SAMPLED BLOOD VOLUME ........................................................................................................ 83 
9.6 
FUTURE USE OF SAMPLES ........................................................................................................ 84 
9.7 
EFFICACY ..................................................................................................................................... 84 
9.7.1 
Criteria for response (antitumoral activity) ..................................................................................... 84 
10 
PATIENT SAFETY ......................................................................................................................... 85 
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL ..................................................................... 85 
10.2 
SAFETY INSTRUCTIONS ............................................................................................................. 85 
10.3 
ADVERSE EVENTS MONITORING .............................................................................................. 85 
10.4 
DEFINITIONS OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT .................................. 85 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 86 
10.5.1 
Adverse events .............................................................................................................................. 86 
10.5.2 
Serious adverse events ................................................................................................................. 86 
10.5.3 
Follow-up ........................................................................................................................................ 87 
10.5.4 
Treatment discontinuation due to nonserious adverse event ........................................................ 87 
10.5.5 
Adverse event of special interest ................................................................................................... 87 
10.5.6 
Laboratory abnormalities ............................................................................................................... 88 
10.5.7 
Guidelines for reporting product complaints .................................................................................. 88 
10.6 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 88 
11 
HANDLING OF PATIENT TEMPORARY AND PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ...................................... 89 
11.1 
PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL MEDICINAL 
PRODUCT(S) ................................................................................................................................. 89 
11.1.1 
List of criteria for permanent treatment discontinuation ................................................................. 89 
11.1.2 
Handling of patients after permanent treatment discontinuation ................................................... 90 
11.2 
REPLACEMENT OF PATIENTS ................................................................................................... 90 
12 
STUDY PROCEDURES ................................................................................................................ 91 
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12.1 
VISIT SCHEDULE .......................................................................................................................... 91 
12.2 
BASELINE EVALUATION .............................................................................................................. 92 
12.3 
BEFORE THE FIRST INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
ON THE FIRST DAY OF TREATMENT ......................................................................................... 93 
12.4 
DURING THE TREATMENT PERIOD OF CYCLE 1 ..................................................................... 93 
12.5 
DURING FURTHER CYCLES ....................................................................................................... 95 
12.6 
END OF TREATMENT VISIT (TO BE PERFORMED WITHIN 30 DAYS AFTER THE LAST 
ADMINISTRATION OF THE INVESTIGATIONAL MEDICINAL PRODUCT) ................................ 97 
12.7 
PERIOD POST END OF TREATMENT ......................................................................................... 97 
12.8 
POST STUDY CUT-OFF PERIOD ................................................................................................ 98 
13 
STATISTICAL CONSIDERATIONS .............................................................................................. 99 
13.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 99 
13.1.1 
Dose escalation part ...................................................................................................................... 99 
13.1.2 
Expansion part ............................................................................................................................... 99 
13.2 
PATIENT DESCRIPTION .............................................................................................................. 99 
13.2.1 
Disposition of patients .................................................................................................................... 99 
13.2.2 
Protocol deviations ....................................................................................................................... 100 
13.3 
ANALYSIS POPULATIONS ......................................................................................................... 100 
13.3.1 
All-treated/safety population ........................................................................................................ 100 
13.3.2 
Patients evaluable for DLT assessment ...................................................................................... 100 
13.3.3 
Pharmacokinetic population ......................................................................................................... 101 
13.3.4 
Activity/efficacy population ........................................................................................................... 101 
13.3.5 
Anti-drug antibody population ...................................................................................................... 101 
13.4 
STATISTICAL METHODS ........................................................................................................... 101 
13.4.1 
Demographics and baseline characteristics ................................................................................ 101 
13.4.2 
Extent of investigational medicinal product exposure .................................................................. 101 
13.4.3 
Prior/concomitant medication/therapy.......................................................................................... 102 
13.4.4 
Analyses of safety data ................................................................................................................ 103 
13.4.4.1 Dose-limiting toxicities.................................................................................................................. 103 
13.4.4.2 Analyses of adverse events ......................................................................................................... 103 
13.4.4.3 Deaths .......................................................................................................................................... 104 
13.4.4.4 Clinical laboratory evaluations ..................................................................................................... 104 
13.4.4.5 Vital signs ..................................................................................................................................... 105 
13.4.4.6 Immunogenicity ............................................................................................................................ 105 
13.4.5 
Analyses of pharmacokinetic variables ........................................................................................ 106 
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13.4.6 
Analysis of cytokines .................................................................................................................... 106 
13.4.7 
Analysis of immunophenotyping data .......................................................................................... 107 
13.4.8 
Analyses of antitumor activity/efficacy variables .......................................................................... 107 
13.5 
INTERIM ANALYSIS .................................................................................................................... 107 
14 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 108 
14.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 108 
14.2 
INFORMED CONSENT ............................................................................................................... 108 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 109 
15 
STUDY MONITORING................................................................................................................. 110 
15.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 110 
15.2 
RESPONSIBILITIES OF SPONSOR ........................................................................................... 110 
15.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 111 
15.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUESTS ......... 111 
15.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 111 
16 
ADDITIONAL REQUIREMENTS ................................................................................................. 112 
16.1 
CURRICULUM VITAE.................................................................................................................. 112 
16.2 
RECORD RETENTION IN STUDY SITES(S) ............................................................................. 112 
16.3 
CONFIDENTIALITY ..................................................................................................................... 112 
16.4 
PROPERTY RIGHTS ................................................................................................................... 113 
16.5 
DATA PROTECTION ................................................................................................................... 113 
16.6 
INSURANCE COMPENSATION .................................................................................................. 113 
16.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 114 
16.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 114 
16.8.1 
By the Sponsor ............................................................................................................................. 114 
16.8.2 
By the Investigator ....................................................................................................................... 115 
16.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 115 
16.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 115 
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17 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 116 
18 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 117 
19 
APPENDICES .............................................................................................................................. 121 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION .................................................................................................... 122 
APPENDIX B 
LIST OF CYP SUBSTRATES WITH A NARROW THERAPEUTIC RANGE .................... 125 
APPENDIX C 
ECOG PERFORMANCE STATUS SCALE ....................................................................... 126 
APPENDIX D 
RESPONSE CRITERIA FOR ALL ..................................................................................... 127 
APPENDIX E 
REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM IN MDS .................... 129 
APPENDIX F 
RESPONSE CRITERIA FOR AML .................................................................................... 130 
APPENDIX G 
RESPONSE CRITERIA FOR HR-MDS ............................................................................ 131 
APPENDIX H 
GRADING SYSTEM AND MITIGATION STRATEGY FOR CRS, BASED ON 2014 
NCI CONSENSUS GUIDELINES ................................................................................................ 134 
APPENDIX I 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS..................................................................................................................... 135 
APPENDIX J 
GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS SYNDROME (TLS). ......... 136 
APPENDIX K PROTOCOL AMENDMENT HISTORY ................................................................................ 141 
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2.1 
LIST OF TABLES  
Table 1 - Intra-patient dose escalation: Cycle 1 ............................................................................................ 55 
Table 2 - Patient dosing after Cycle 1 ........................................................................................................... 56 
Table 3 - Dose Escalation Part from DL1 to DL8 .......................................................................................... 56 
Table 4 - Definition of dose steps .................................................................................................................. 59 
Table 5 - Recommendations for resumption of treatment and dose modification following infusion-related 
reactions during SAR440234 infusion ........................................................................................................... 61 
Table 6 - Recommendations for resumption of treatment and dose modification following cytokine release 
syndrome after SAR440234 infusion is completed ....................................................................................... 61 
Table 7 - Dose delays and modifications for hematological adverse events ................................................ 63 
Table 8 - Dose delays and modifications for bone marrow hypocellularity Grade 4 ..................................... 63 
Table 9 - Dose delay and dose modification for adverse events not including hematological adverse 
events, cytokine release syndrome, or infusion-related reactions ................................................................ 65 
Table 10 - Grading of cytokine release syndrome according to 2014 National Cancer Institute Consensus 
Guidelines ...................................................................................................................................................... 66 
Table 11 - Evaluation and management of cytokine release syndrome ....................................................... 67 
Table 12 - High dose vasopressors ............................................................................................................... 67 
Table 13 - List of pharmacokinetic parameters and definitions ..................................................................... 82 
 
2.2 
LIST OF FIGURES  
Figure 1 - SAR440234 structure .................................................................................................................... 44 
 
 
 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
ADI: 
actual dose intensity 
AESI: 
adverse event of special interest 
ALL: 
acute lymphocytic or lymphoblastic leukemia 
ALT: 
alanine aminotransferase 
AML: 
acute myeloid leukemia 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
BUN: 
blood urea nitrogen 
CR: 
complete response  
CRi: 
complete response with incomplete hematological recovery 
CRO: 
contract research organization 
CRP: 
C-reactive protein 
CRS: 
cytokine release syndrome 
CTC: 
common terminology criteria 
DLT: 
dose-limiting toxicity 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
FIH: 
first-in-human 
GCP: 
good clinical practice 
GGT: 
gamma glutamyl transferase 
GLP: 
Good Laboratory Practice 
GM-CSF: 
granulocyte macrophage-colony stimulating factor 
HR-MDS: 
high risk myelodysplasia 
HSC: 
hematopoietic stem cells 
ICH: 
International Council for Harmonisation 
ICU: 
intensive care unit 
IEC: 
institutional ethics committee 
IFN: 
interferon 
Ig: 
immunoglobulin 
IL: 
interleukin 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IV: 
intravenous 
IWG: 
International Working Group 
LSC: 
leukemic stem cell 
LSC: 
leukemic stem cell 
MABEL: 
minimal anticipated biological effect level 
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MAD: 
maximum administered dose 
MDS: 
myelodysplastic syndrome 
MRD: 
minimal residual disease 
MTD: 
maximum tolerated dose 
NCCN: 
National Comprehensive Cancer Network 
NCI: 
National Cancer Institute 
NIMP: 
noninvestigational medicinal product 
ORR: 
overall response rate 
PD: 
progressive disease 
PO: 
orally 
R/R AML: 
relapsed or refractory acute myeloid leukemia 
RDI: 
relative dose intensity 
R-IPSS: 
Revised International Prognostic Scoring System 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SD: 
stable disease 
StD: 
standard deviation 
TCE: 
T-cell engager 
TEAE: 
treatment-emergent adverse event 
TLS: 
Tumor lysis syndrome 
TNF: 
tumor necrosis factor 
ULN: 
upper limit of normal 
WHO: 
World Health Organization 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is the 
leading cause of fatal leukemia in the United States. First-line treatment for AML has changed 
little over the last 30 years, although the approval of 3 new drugs for AML in 2017, midostaurin 
(1), enasidenib (2), and CPX-351, suggests that a new era of AML therapy is beginning. AML 
induction regimens typically include cytosine arabinoside and anthracyclines. Allogeneic stem 
cell transplant is offered to patients with high risk disease in first or subsequent remissions. 
Despite this aggressive therapeutic approach, from 2007 to 2013 only 26.9% of patients diagnosed 
with AML survived 5 years (3). Relapse of AML is common and salvage treatment with cytotoxic 
chemotherapy is rarely curative (4). 
There is growing evidence to suggest that AML derives from leukemic stem cells (LSCs) that 
give rise to leukemic blasts in vitro and in vivo models. It is hypothesized that the persistence of 
LSCs causes relapse after an initial remission. Thus the eradication of LSCs may be a requirement 
for cure and is an important therapeutic goal. One potential therapeutic target in AML is the 
surface receptor CD123, the interleukin (IL)-3 receptor alpha chain (IL-3R α) that is expressed at 
high levels on LSCs. Similar to normal hematopoietic stem cells (HSCs), LSCs have been shown 
to express CD34, but lack CD38 (CD34+CD38-), as well as other markers. While CD123 is 
expressed in both normal HSCs and AML LSCs, CD123 is expressed in a higher proportion of 
AML LSCs than normal HSCs (5, 6, 7, 8) and is more intensely expressed on AML LSCs than 
normal HSCs (9, 10, 11). 
CD123 is strongly expressed in LSCs and blasts in the majority of patients with AML, regardless 
of prognostic risk group based on cytogenetic and molecular analysis (12). CD123 is also 
expressed in a variety of other hematologic malignancies, including myelodysplastic syndrome 
(MDS), B lineage acute lymphocytic or lymphoblastic leukemia (B-ALL), Hodgkin lymphoma, 
hairy cell leukemia, and chronic myeloid leukemia (7, 11, 13, 14). 
No CD123-targeted therapy has been approved yet, but novel therapies targeting CD123 are 
currently under development, either as monoclonal antibodies, antibody drug conjugates 
(NCT02848248, NCT01632852, NCT02472145), or bispecific antibodies (NCT02715011, 
NCT02152956, NCT02730312). T-cell engagers (TCE) are bispecific molecules that aim to 
enhance the patient’s immune response to tumors by stimulating the patient’s T-cells to attack 
tumor cells. 
SAR440234 is a monoclonal antibody TCE that is being developed as a potential therapy for 
hematologic malignancies. One arm of SAR440234 targets the CD3ε subunit of the T-cell 
co-receptor at the surface of the T-cell. The other arm targets CD123 on the malignant cell. 
Co-engagement of T-cell and malignant cell by the bispecific construct leads to the formation of a 
cytolytic synapse that induces T-cell activation and results in tumor cell specific killing. This 
process is human leukocyte antigen-independent, but requires the presence of the selected tumor 
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antigen at the surface of the tumor cell. Clinical proof of concept of T-cell redirected tumor cell 
killing has been achieved by the registration of blinatumomab, Blincyto®, a CD19-CD3 TCE for 
the treatment of ALL. 
Despite advances in understanding the pathophysiology of AML and recognizing its molecular 
heterogeneity, developing viable therapeutics for patients with AML has proved to be a challenge. 
Novel agents are needed to achieve better responses that prolong overall survival, particularly for 
patients with relapsed or refractory disease. Consequently the proposed primary indication is 
relapsed or refractory acute myeloid leukemia (R/R AML) and high risk myelodysplasia 
(HR-MDS) patients who are ineligible for or have exhausted standard therapeutic options. As 
B-ALL leukemic cells often express CD123, this population is also included in the 
Dose Escalation Part. If B-ALL patients tolerate the study treatment well, SAR440234 may be 
investigated further in this population in subsequent studies. 
4.2 
SAR440234  
SAR440234 (CD3-CD123 TCE) is a humanized bispecific monoclonal antibody that binds 
selectively to the human CD123 tumor antigen and CD3 subunit of the T-cell co-receptor.  
The structure is composed of a CODV-Fab fragment (CL kappa/CH1) grafted to an Fc IgG1 with 
LALA mutation to suppress Fc effector function (light chain position 366/367; heavy chain 
position 358/359). The so-called light chain is composed of 578 amino acids and has a molecular 
weight of 63 035.52 Da; the heavy chain is composed of 570 amino acids and has a molecular 
weight of 62800.90 Da. 
The structure is illustrated in Figure 1. 
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Figure 1 - SAR440234 structure  
 
SAR440234 (LC80781, [hz20G6 x hz7G3-N55S with Fc-IgG1-LaLa backbone]) is a novel fully 
human bispecific antibody TCE molecule that is proposed for the treatment of cancer. The 
proposed primary indication for SAR440234 CD3-CD123 TCE is AML. 
SAR440234 is designed to simultaneously bind CD3, the human T-cell co-receptor molecule, and 
CD123, the human IL3 receptor alpha chain subunit (IL-3Rα) and thereby co-engage T-cells with 
CD123-expressing tumor cells, resulting in presentation of tumor cells for T-cell directed 
tumor-specific killing. 
CD123 is aberrantly over-expressed in AML and in other hematological malignancies (MDS, 
systemic mastocytosis, blastic plasmacytoid dendritic cell neoplasm, B-ALL, and hairy cell 
leukemia). CD123 is expressed on AML blasts (~80% of positive samples, 63% with more than 
80% CD123-positive blasts) and on CD34-positive/CD38-negative AML leukemic stem cells 
(~90% CD123-positive LSCs) (12). It has little expression outside the hematopoietic system. 
Thus, CD123 represents an attractive target for therapy in patients with AML. 
In vitro studies have shown that SAR440234 induces T-cell activation and cytotoxic activity. 
Inhibition of AML tumor cell growth was seen with SAR440234 in animal tumor models. 
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4.3 
NONCLINICAL TOXICOLOGY  
Based on significant sequence homology of human CD3ε and CD123 compared to cynomolgus 
monkey in contrast to rodents, on similar binding affinity to both targets for human and 
cynomolgus monkey, and on overall similar staining pattern in cross-reactivity studies performed 
with SAR440234 on human and cynomolgus monkey normal tissues, the cynomolgus monkey 
was selected as the relevant species for in vivo toxicology evaluation. 
Tissue cross-reactivity using normal human and cynomolgus monkey frozen tissues was assessed 
by immunohistochemistry using SAR440234 conjugated with digoxigenin (SAR440234-DIG). 
SAR440234-DIG-specific staining was observed in lymphoid tissues, bone marrow and on 
infiltrating/circulating cells and/or endothelial cells in most tissues in both species demonstrating 
overall similar staining distribution on human and cynomolgus monkey tissues. The localization 
of the staining was as expected, based on the reported distribution of CD3 and CD123 antigens. 
Consequently, the in vivo general toxicity studies were conducted in cynomolgus monkeys, only. 
In the repeat-dose monkey studies, a progressive weekly intra-monkey dose escalation was used 
in an attempt to mitigate the cytokine release observed after a single administration. The doses 
used in the 3 conducted monkey toxicity studies were: 
 in the single-dose 
exploratory study, 
 in the weekly (x4) 
exploratory study and 
 
(3 males), and 
 (5 females) in the weekly (x6) Good Laboratory Practice 
(GLP) study. 
Safety pharmacology endpoints were evaluated in the weekly monkey GLP study. No 
SAR440234-related effects were noted on electrocardiogram (ECG), blood pressure and 
respiration rate in this study up to the highest dose tested of 
 Transient 
clinical signs and transient increased body temperature noted in the study were considered a 
consequence of the cytokines release and not a direct effect of SAR440234 on the central nervous 
system. 
The main adverse effects noted in monkeys consisted of marked increases in the levels of 
cytokines (IL-2, IL-6, IL-10, interferon [IFN]γ and/or tumor necrosis factor [TNF]α) within the 
24 hours following compound administration at 
 and above, associated with transient 
clinical signs (such as raised hair, hunched posture, impaired mobility, subdued/sluggish behavior, 
lethargy and/or emesis), transient increases in body temperature within the 24 hours following 
compound administration and transient increases in C-reactive protein (CRP) and ferritin 
(evaluated in the weekly monkey GLP toxicity study only). These effects resulted in preterminal 
euthanasia of the monkeys in the single-dose and weekly monkey GLP studies at high doses of 
7.5 μg/kg and above. 
The main target organs identified in the animals that were euthanized at scheduled necropsy 
consisted of minimally increased cellularity of intravascular neutrophils in the lungs in the 
single-dose monkey study and minimal to slight increased germinal centers in the spleen in the 
weekly GLP monkey study. 
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In addition, minimal to mild and transient increases in aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, bilirubin and/or fibrinogen were 
noted mainly in the single-dose monkey study. 
The local tolerance of SAR440234, evaluated in the weekly monkey GLP study, was good, as no 
compound-related macroscopic or microscopic findings were noted at the injection sites at any 
dose level. 
Overall, test article-treated monkeys were exposed to SAR440234, with quantifiable plasma 
concentrations at least at the end of the 1-hour intravenous (IV) infusion (Ceoi). After repeated 
administration, Ceoi were maintained throughout the different administrations at 
, but 
decreased dramatically at 
 after the fourth administration, most probably due to the 
presence of anti-drug antibody (ADA, ie, anti-SAR440234 antibody) in the majority of the 
animals. Consequently, cytokine release mitigation by progressive intra-monkey dose escalation 
was demonstrated in the weekly monkey exploratory study at the dose of 
 only. It was not 
possible to conclude on mitigation in the weekly monkey GLP study due to the dramatic decrease 
in exposure after repeated administration. 
Modulation of pharmacodynamic biomarkers in blood and/or bone marrow (depletion of 
CD123+ cells) was evidenced in the 3 monkey studies from the lowest dose tested 
 
and this dose was the no-observed adverse effect level in these 3 monkey studies. 
Most of the effects of SAR440234 described above are perfectly in line with the review article on 
17 Investigational New Drugs (different CD3 bispecific formats) published by FDA in 
September 2017: “An FDA oncology analysis of CD3 bispecific constructs and first-in-human 
dose selection”(15). 
4.4 
PHARMACOKINETICS IN ANIMAL  
The nonclinical pharmacokinetics of SAR440234 were investigated in the toxicological species 
(cynomolgus monkeys) following an IV (1-hour infusion) administration of 3H-SAR440234 to 
overcome the limitation of the immunoassay sensitivity. Following a single IV (1 hour) 
administration to cynomolgus monkeys, the radioactivity exhibited a bi-compartmental 
pharmacokinetic profile. The volume of distribution ranged from 
 and clearance 
ranged from 
. Terminal elimination half-life was around 
 
Exposure assessed by area under the curve (AUC) increased slightly less than expected by dose 
increase, with a 
 increase in AUC for a 
 increase in dose 
. 
As the drug substance is a therapeutic protein, no other evaluation was conducted for absorption, 
distribution, elimination or excretion. It is generally recognized that antibodies are metabolized by 
degradation into small peptides and individual amino acids following endogenous catabolism, 
therefore no metabolism studies were conducted. 
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4.5 
STUDY DESIGN RATIONALE  
4.5.1 Choice of starting dose  
The first-in-human (FIH) study is proposed as a single agent trial in patients with R/R AML, 
HR-MDS, and B-ALL. This trial is intended to establish proof-of-concept for this drug, based on 
clinical, pharmacokinetic, and biomarker evaluation; to assess the safety and preliminary 
anti-leukemic activity of SAR440234; and to define the optimal single agent dose for future 
studies. The FIH Phase 1/2A study will include a Dose Escalation Part to determine the 
recommended dose, followed by an Expansion Part at the recommended Phase 2 dose (RP2D). 
SAR440234 falls into the class of potent immunomodulatory agonists, and as recommended by 
ICHS9 guidances, it is proposed to use a conservative minimal anticipated biological effect level 
(MABEL) approach to define the starting dose for the FIH study. 
The most sensitive and relevant assays using in vitro human material were selected for the 
MABEL determination. The anti-tumor efficacy of SAR440234 on disseminated human primary 
AML in vivo in the NSG mouse model was not incorporated in the MABEL determination, as the 
translational value of this model was uncertain.  
In vitro, in a depletion assay using peripheral blood mononuclear cells from human healthy 
donors, SAR440234 depleted CD123-positive monocytes with a first effective concentration 
producing 80% effect (EC80) of 
. This activity was associated with 
a 20% cell depletion. 
The MABEL was calculated using the most sensitive data on CD123-positive cell depletion  
(
MABEL
C
) with pharmacokinetic modeling to determine the FIH dose, according to the equation: 
human
MABEL
Vc
C
Dose


. It is a conservative approach (Duff method, 2006 [16]), assuming the 
total dose is administered as a bolus and instantly distributed into total plasma volume. 
human
C
V
, volume of the central compartment in human, was obtained from pharmacokinetic 
parameters determined in monkeys from 2-compartment model analysis and scaled to human, 
according to the following equation: 









monkey
human
monkey
human
BW
BW
Vc
Vc
, with 
human
BW
=70 kg, 
monkey
BW
=3 kg and =1 (17) 
human
C
V
 was determined as 
  
The FIH dose was determined as 
kg
ng
kg
mL
mL
ng
Dose
/
/
/



 and the nearest 
convenient dose was set to 1 ng/kg. 
In conclusion, the recommended starting dose for FIH administration is 
 
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4.5.2 Clinical rationale  
The proposed primary indications for SAR440234 are R/R AML, and HR-MDS. As discussed 
above, CD123 is highly expressed in most AML blasts, on CD3-positive/CD38-negative AML 
leukemic stem cells, and in B-ALL cells (18). CD123 has little expression outside the 
hematopoietic system. For these reasons, CD123 is an important therapeutic target in patients with 
AML and other hematologic malignancies that express CD123. 
Because CD123 is expressed in the leukemic blasts from a majority of patients with AML, the 
selection of patients for CD123-expressing leukemic blasts in the FIH phase 1 is not 
recommended. Nonetheless, in vitro experiments have demonstrated that CD123 density might 
influence SAR440234 efficacy (sanofi, unpublished data). Thus, in the clinic, CD123 expression 
prevalence and cell density will be monitored in leukemic cells, blasts and LSCs, and in normal 
cells known to express CD123, such as basophils, plasmacytoid dendritic cells, and monocytes. 
The depth of CD123-positive cell depletion will be utilized as a pharmacodynamic monitoring 
marker of SAR440234 efficacy. 
In the literature, very little has been reported about the T-cell subpopulation presence and state of 
activation or exhaustion in patients with AML. Because SAR440234’s mechanism of action relies 
on its ability to recruit and activate T-cells, T-cell sub-populations will be monitored in the 
FIH study. In addition to monitoring CD123-expression and T-cell sub-populations, clinical sites 
participating in the testing of SAR440234 will be asked to provide data on the cytogenetic profile 
and molecular alterations observed in the leukemic cells of AML and MDS patients entering the 
clinical trial, as is now routine in the risk-stratification of AML and MDS patients (19). The sites 
will be required to obtain and record the results in the clinical database. 
4.5.3 SAR440234 dose and regimen  
A dose escalation single agent trial will be initiated in patients with R/R AML, HR-MDS, and 
B-ALL. This trial is intended to establish proof-of-concept for this drug, based on clinical, 
pharmacokinetic, and biomarker evaluation; to assess the safety and preliminary anti-leukemia 
activity of SAR440234; and to define the optimal dose of drug as a single agent. 
Use of intra-patient dose escalation is proposed. This dosage strategy has already demonstrated its 
benefit in approved drugs, such as Blincyto®, with the same objective of cytokine release 
syndrome (CRS) mitigation. The strategy of intra-patient dose escalation is currently being used 
for other drugs under development. 
In the first 2 dose levels (DL1 and DL2), SAR440234 will be administrated once weekly. After 
evaluation of the first 2 dose levels, a 2-step dosing increase in the first week of administration 
will be implemented to reach higher exposure in a shorter time frame. 
A weekly schedule (bi-weekly during Cycle 1, Week 1 in DL ≥3) will be evaluated with drug 
administration on Days 1, 4 (DL ≥3 only), 8, 15, 22, 29, and 36 of a 6-week cycle that will be 
repeated, provided that the patient is achieving clinical benefit.  
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Cycles run consecutively so that Day 1 of each cycle is normally 7 days after the start of the last 
infusion in the previous cycle. If bone marrow hypocellularity Grade 4 or hematological toxicity 
Grade 3 or 4 is diagnosed, the interval between doses must be extended until toxicity is resolved. 
If the interval between doses is or exceeds 10 days, the treatment must be restarted with the 
lead-in doses appropriate for the selected dose level. 
Systematic premedication with the corticosteroid, dexamethasone (two doses of 20 mg IV), and 
leukotriene inhibitor montelukast (one dose of 10 mg by mouth) are planned starting with the first 
dose of SAR440234 tested. Dexamethasone and/or tocilizumab will be used to treat Grade ≥2 
CRS, as described below and in Section 6.7. Dexamethasone has been chosen because it 
penetrates the blood-brain barrier (20). 
Use of intra-patient dose escalation is proposed. This dosage strategy has already demonstrated its 
benefit in approved drugs, such as Blincyto®, with the same objective of CRS mitigation. The 
strategy of intra-patient dose escalation is currently being used for other drugs under development, 
as well. 
4.5.4 Cytokine release syndrome  
Cytokine-associated toxicity, also known as CRS, is a nonantigen specific toxicity that occurs as a 
result of potent immune activation. It manifests clinically when large numbers of lymphocytes 
(B-cells, T-cells, and/or natural killer cells) and/or myeloid cells (macrophages, dendritic cells, 
and monocytes) become activated and release inflammatory cytokines. Cytokine release syndrome 
has classically been associated with therapeutic monoclonal antibody infusions and in these 
settings, symptom onset typically occurs within minutes to hours after the infusion begins (21, 22, 
23). Cytokine release syndrome has also recently been reported following administration of 
bispecific antibodies for leukemia, infusion of haploidentical mononuclear cells to patients with 
refractory leukemia, and adoptive immunotherapies for cancer, most notably T-cells engineered to 
express chimeric antigen receptors (18, 24, 25, 26, 27). 
The timing of symptom onset and CRS severity depends on the inducing agent and the magnitude 
of immune cell activation. The incidence and severity of the syndrome also appears greater when 
patients have large tumor burdens, presumably because this leads to higher levels of 
T-cell activation. As with CRS associated with monoclonal antibody therapy, CRS associated 
with adoptive T-cell therapies has been associated with elevated IFN-γ, IL-6, and TNFα levels, 
and increases in IL-2, granulocyte macrophage–colony-stimulating factor (GM-CSF), IL-10, IL-8, 
IL-5, and fractalkine have also been reported (26, 28). Emerging evidence implicates IL-6 as a 
central mediator of toxicity in CRS. IL-6 is a pleiotropic cytokine with anti-inflammatory and 
proinflammatory properties. However, real time analysis of a broad panel of cytokines will not 
significantly impact management of individual patients with CRS, thus it is recommended that 
treatment decisions are based on clinical parameters (29). 
In this FIH trial, plasma levels of cytokines, including IL-6 and IFN-γ, will be collected, as well 
as assays for serum CRP and ferritin. Sampling will be performed following the initial dose and 
after each dose increase, in order to assess for signs of CRS. C-reactive protein is an acute phase 
reactant produced by the liver, largely in response to IL-6. Serum CRP levels may serve as a 
surrogate for increases in IL-6 bioactivity (30). During CRS, serum CRP levels may increase by 
several logs. The serum CRP assay is rapid, inexpensive, and readily available in most hospitals. 
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In some series, peak CRP levels and fold-change in CRP have identified patients at risk for severe 
CRS (26). It is important to emphasize, however, that CRP levels are also elevated during 
infection and cannot be used to distinguish between inflammation caused by infection and 
inflammation related to CRS. Extreme elevations in serum ferritin have been observed in many 
patients with CRS after chimeric antigen receptor T-cell infusion, which supports a resemblance 
between CRS and macrophage activation syndrome/hemophagocytic lymphohistiocytosis. 
To assess and record the severity of CRS in individual patients, the National Cancer Institute 
(NCI) Consensus Guidelines 2014 will be used (29, 31), and the mitigation strategy for CRS 
(Appendix H), is based on these guidelines. This grading system defines mild, moderate, severe, 
and life-threatening CRS, regardless of the inciting agent, and provides treatment 
recommendations with corticosteroids and/or tocilizumab (29). Tocilizumab is a humanized, 
immunoglobulin (Ig)G1k antihuman IL-6R mAb approved for treatment of rheumatoid arthritis, 
juvenile idiopathic arthritis, and polyarticular juvenile rheumatoid arthritis (32, 33). Emerging 
clinical experience at several institutions has demonstrated that tocilizumab is an effective 
treatment for severe or life-threatening CRS (28). The FDA has approved tocilizumab for the 
treatment of chimeric antigen receptor T-cell induced severe or life-threatening CRS. The 
recommended dose of tocilizumab for treatment of CRS is 12 mg/kg IV for patients weighing 
<30 kg and 8 mg/kg IV for patients weighing ≥30 kg. Doses of tocilizumab should not exceed 
800 mg per infusion. It is also recommended that tocilizumab should not be started in patients 
with an absolute neutrophil count (ANC) <2000/microliter, platelet count <100 000/microliter, or 
with an ALT or AST >1.5 times the upper limit of normal (ULN). 
4.6 
BENEFIT RISK ASSESSMENT  
Severe CRS is an anticipated risk due to release of cytokines following T-cell activation. Anemia, 
leukopenia, and thrombocytopenia are other anticipated risks that commonly occur during 
treatment for hematologic malignancies. The safety monitoring and risk mitigation plan includes 
the following measures: 
 Systematic premedication with dexamethasone and montelukast will be provided starting 
with the first dose of SAR440234 tested.  
 Treatment with tocilizumab will be started if CRS Grade 2 is diagnosed. Two doses of 
tocilizumab will be available on site for each patient under treatment. 
 A conservative MABEL approach is planned to define a very low dose as the starting dose 
in humans.  
 Careful intra-patient dose escalation with conservative increases for each dose level will 
be performed. The dose escalation cohort will be initiated at a lower dose at the first 
infusion in each patient. The purpose of this design is to minimize exposure to 
sub-therapeutic doses while maintaining patient safety, particularly in the context when the 
FIH starting dose is very low. This strategy will facilitate rapid attainment of active 
therapeutic doses. 
 Extensive clinical monitoring will be conducted during the Dose Escalation Part, including 
frequent assessment of vital signs during infusion and at specific time points post infusion. 
During Cycle 1 and the first 2 doses of Cycle 2 in the Dose Escalation Part, patients will 
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be hospitalized for the duration of each SAR440234 infusion (1 to 19 hours) and for the 
first 72 hours after the infusion is completed. During Cycle 1 and the first 2 infusions of 
Cycle 2 in the Expansion Part, patients will be hospitalized for the duration of the 
SAR440234 infusion (1 to 19 hours), and for 72 hours after completion of each infusion. 
During the remaining infusions of Cycle 2 and beyond in the Expansion Part, if the patient 
has tolerated the SAR440234 infusion well, the patient will be hospitalized only for the 
duration of each subsequent infusion (1 to 19 hours). The 2014 NCI Consensus Guidelines 
will be used to grade and guide the management of CRS (Appendix H). 
 A DLT observation period of 42 days from the first administration of IMP in the first 
cycle, with administration of IMP on Day 1, Day 4 (DL ≥3), Day 8, and weekly thereafter, 
including at least 3 maximal subsequent doses in each dose level, will be followed to 
monitor for delayed effects of SAR440234 and for effects that occur only after the highest 
dose in Cycle 1. 
 Continuous monitoring of vital signs will be implemented if CRS Grade ≥2 develops; 
blood chemistry will be tested every 8 hours. Any patients with Grade 2 or greater CRS 
must be admitted to the ICU.  
 During the first cycle, patients will be monitored every 8 hours after the start of IMP 
administration and for at least 72 hours after the end of the SAR440234 infusion for signs 
and symptoms of tumor lysis, including serum creatinine, potassium, magnesium, 
phosphorous, calcium, and uric acid. 
 Complete blood counts including white blood cell differential and ANC will be assessed 
daily during Cycle 1, the first 2 weeks of Cycle 2, and weekly thereafter for the duration of 
the treatment. Patients who develop Grade 3 or Grade 4 febrile neutropenia should receive 
broad spectrum antimicrobial therapy according to the hospital site's protocol. SAR440234 
treatment should be discontinued for Grade 4 febrile neutropenia. Transfusion with red 
blood cells and platelets should be provided as needed. 
 The study will be conducted at a limited number of sites, which will be selected based on 
their experience with potent immune modulating agents, treatment of leukemia, and CRS. 
Appropriate training will be provided, and the sites will be closely monitored.  
The product is intended to be administered by IV infusion after reconstitution and dilution of 
lyophilized drug product in single use vials. While designing the strategy to ensure accuracy and 
control of the actual dose administered in each dose level, the following factors were considered: 
the extremely low starting dose, the wide range of doses expected during the dose escalation, the 
high potency of SAR440234, the risk of CRS, and the intended concentration of drug product 
formulation proposed for the FIH study. Hospital sites will be selected based on their 
demonstrated experience in complex administration procedures. Training will be reinforced at the 
sites, and procedures specified to minimize the risk of human error during dilution and potential 
product adsorption during drug preparation and infusion. The clinical administration protocol 
guidelines have been developed accordingly. 
A solution for coating is supplied with SAR440234 that is used to coat infusion bags prior to 
dilution, which prevents adsorption of SAR440234 onto bags and infusion materials. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY OBJECTIVES:  
Dose Escalation Part 
 To determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) of 
SAR440234 administered as a single agent in patients with R/R AML, HR-MDS, or 
B-ALL and determine the recommended Phase 2 dose (RP2D) for the subsequent 
Expansion Part. 
Expansion Part 
 To assess the activity of single agent SAR440234 at the RP2D in patients with R/R AML 
or HR-MDS. 
5.2 
SECONDARY OBJECTIVES:  
 To characterize the safety profile of SAR440234 including cumulative adverse drug 
reactions. 
 To characterize the pharmacokinetic profile of SAR440234 when administered as a single 
agent.  
 To evaluate the potential immunogenicity of SAR440234.  
 To assess any preliminary evidence of hematologic response in the Dose Escalation Part.  
5.3 
EXPLORATORY OBJECTIVES:  
To perform pharmacodynamic assessments on blood and bone marrow including: 
 To measure CD123 expression in malignant cells and kinetics of this expression under 
treatment.  
 To monitor CD123 expression on normal cells. 
 To assess minimal residual disease (MRD) in patients achieving a complete response (CR) 
or complete response with incomplete hematological recovery (CRi), and correlate MRD 
with clinical outcome. 
 To assess T-cell subpopulations (eg, CD4, CD8) and activation status. 
 To investigate the relationship between CD123 expression, disease molecular subtype 
(as defined by marker expression, cytogenetics, and/or genomics) and parameters of 
clinical response. 
To assess levels of cytokines following treatment administration, and their relationship with safety 
profile and clinical outcome. 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
Sequential cohort(s): 
This Phase 1/2A Study is an open-label, nonrandomized, dose escalation and dose expansion, 
safety, efficacy, pharmacokinetic, and pharmacodynamic evaluation study of SAR440234 
administered as a single agent IV infusion every week to patients ≥16 years of age with 
R/R AML, HR-MDS, or B-ALL. 
The study will be performed in 2 parts: a Dose Escalation Part and an Expansion Part both with 
SAR440234 used as monotherapy. Enrollment of patients in the Expansion Part will start after 
completion of the Dose Escalation Part and identification of the MTD/RP2D. 
6.2 
STARTING DOSE AND DOSE ESCALATION PART  
The rationale for selecting the starting dose and the dose escalation design are described in 
Section 4.5.1 and in Section 1.1, respectively. 
6.2.1 Starting dose and dose levels  
SAR440234 will be administered IV on Day 1, Day 4 (DL ≥3), Day 8, and weekly thereafter in 
Cycle 1 for a 42-day cycle. The dosing regimen will be weight-based; however, if a patient 
weighs >140 kg, the patient’s weight will be capped at 140 kg for dose calculations. The 
administration of the investigational medicinal product (IMP) will begin at 
, representing 
the selected safe starting dose for an FIH trial, based on the MABEL, and by integration of all 
available in vivo and in vitro data at the start of the study.  
A 3+3 dose escalation scheme will be used, based on DLTs observed during the first 42 days 
following the first administration of IMP in the first cycle (the DLT observation period). The goal 
is to treat 3patients per dose level in order to follow a 3 +3 design. In this FIH study, potential 
DLTs are defined as the following: 
 Any Grade ≥3 nonhematological AE, unless either caused by disease progression or an 
obviously unrelated cause or caused by a laboratory abnormality without associated 
clinical consequences that resolves within 5 days (AE’s related to cytopenias that were 
present prior to starting SAR440234 or to underlying leukemia will not be considered 
DLT’s).  
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 Grade 4 hematological toxicities as defined in NCI-CTCAE v4.03, ie, new onset or 
worsening of life-threatening hematological abnormalities after administration of 
SAR440234 (AE’s related to cytopenias that were present prior to starting SAR440234 or 
to underlying leukemia will not be considered DLT’s).  
- 
Grade 4 bone marrow hypocellularity, if not caused by disease progression and not 
improved to baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 decreased neutrophils, if not present at baseline and not resolved to 
baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 febrile neutropenia not resolved within 7 days, 
- 
Grade 4 decreased platelet count, if not present at baseline and not improved to 
baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 anemia, if not improved to baseline value or Grade ≤1 within 14 days. 
 Grade 3 or Grade 4 CRS. 
 Grade 2 CRS if it persists for >48 hours or is present <48 hours before the time when the 
next planned dose of SAR440234 is due. 
 Any treatment-emergent adverse event (TEAE) that, in the opinion of the Principal 
Investigator and Sponsor, is of potential clinical significance such that further dose 
escalation would expose patients to unacceptable risk. 
 IMP-related adverse reaction (unless caused by disease progression or an obviously 
unrelated cause) lasting more than 2 weeks with failure to recover to baseline or improve 
to Grade ≤1. 
During the Dose Escalation Part, escalation to the next dose level cohort will occur after the last 
patient has completed the DLT observation period for the previous dose level. Within a dose 
level, subsequent patients will initiate treatment at least 1 week after the first patient in that dose 
level started treatment with SAR440234. 
The occurrence of DLTs will inform the dose recommendation that will be used during the 
Expansion Part. 
Response will be evaluated by a bone marrow aspirate at the end of Cycle 1 (Day 42 ±2 days). 
Patients may continue treatment with the IMP as long as clinical benefit is possible, or until 
disease progression, unacceptable adverse reaction, patient’s decision to stop the treatment, or 
other reason for discontinuation (Section 6.5). Bone marrow aspirate will be performed on Day 42 
(±2 days) of Cycle 2. Additional bone marrow aspirate is required if onset of cytopenia >14 days 
before or after Day 42. Subsequent bone marrow aspirates will be performed when clinically 
indicated, as determined by the treating physician. Additional bone marrow aspirate shall be 
performed as clinically indicated or if any of the following occurs: if decreased neutrophil count 
Grade 4, decreased platelet count Grade 4, febrile neutropenia Grade 3 and Grade 4, or anemia 
Grade 4 occurs with onset in >14 days before or after Day 42. 
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Response assessment will be performed according to the International Working Group (IWG) 
2003 recommendations for AML (19) and the revised 2000 criteria for HR-MDS (34), and the 
2016 National Comprehensive Cancer Network (NCCN) Guidelines for ALL (Appendix D, 
Appendix F, and Appendix H).  
If at the end of a cycle the patient exhibits clinical benefit by symptoms or response criteria and 
does not meet study treatment discontinuation criteria, the patient may continue therapy until an 
unacceptable AE, disease progression, patient's decision to stop the treatment, or any other reason. 
To minimize the risk of severe CRS, an intra-patient dose escalation in Cycle 1 is proposed, as 
shown in Table 1. Lead-in doses include the first 2 doses in DL1 and DL2 (ie, Week 1 and 
Week 2 administered doses), the first 3 doses in DL3 to DL5, and the first 4 doses in DL6 to DL8. 
After the lead-in doses, each patient will receive a fixed dose until the end of treatment, unless the 
dose needs to be decreased for safety reasons. DL1 to DL8 will achieve a range of lead-in doses 
from 
 and a range of final doses from 
. During each cycle, 
pharmacokinetic and pharmacodynamic data will be collected that will be used, together with 
acute safety monitoring, in both the Dose Escalation and Expansion Parts. 
Table 1 - Intra-patient dose escalation: Cycle 1  
Dose Level 
Cycle 1 (doses in ng/kg) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Day 1 
Day 4 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
DL8 
DL=dose level 
For subsequent cycles, patients will maintain the maximum weekly dose that they achieved in 
Cycle 1, as shown in Table 2. 
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Table 2 - Patient dosing after Cycle 1  
Dose Level 
Cycle ≥2 (doses in ng/kg) 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
DL1 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
DL8 
DL=dose level 
6.2.2 Dose-limiting toxicity  
The DLT observation period is 42 days from the first administration of IMP in the first cycle, with 
administration of IMP on Day 1, Day 4 (DL ≥3), Day 8, and weekly thereafter. A new dose level 
may begin 42 days after the last patient at a particular dose level receives his or her first dose of 
SAR440234. 
The goal is to treat 3 patients per dose level in order to follow a 3 +3 design. For a given dose 
level, the second and third patients will be treated after the first patient at this dose level has been 
treated for 1 week. In the event of a DLT, the dose level will be expanded to a total of 6 patients, 
who will be treated at the same dose level that the DLT occurred (3 +3 design). If 1 of the 
6 patients experience an IMP-related DLT at the dose level, the dose escalation will proceed with 
3 patients per dose level. If ≥2 of 6 patients experience an IMP-related DLT, the MAD has been 
reached and the dose escalation will be stopped. The dosing plan for DL1to DL8 is summarized in 
Table 3. 
Table 3 - Dose Escalation Part from DL1 to DL8  
DLT observed at Cycle 1, in the first 3 patients 
DLT observed in the whole cohort 
DLT in 0/3  escalate to the next dose level 
- 
DLT in 1/3  add 3 more patients at the same level 
- 1 DLT/ 6 patients  escalate to the next level 
- ≥2 DLTs/ 6 patients  define MAD  
DLT in ≥2/3  no additional patients 
Defines MAD 
DLT=dose-limiting toxicity; MAD=maximum administered dose 
Inclusion of B-ALL patients 
At any DL ≥3, patients with B-ALL (see inclusion criterion I 01) may also be recruited in the 
Dose Escalation Part.  
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Study continuation 
The duration of each cycle of treatment is 42 days, with weekly administration of IMP (except for 
Cycle 1 Week 1 in DL ≥3 when 2 administrations will be given).  
The criteria for retreatment of patients are described in Section 6.5. 
The dose given in the second or subsequent cycles will be the last dose given in the previous 
cycle. If there is a ≥10-day interval between administrations of SAR440234, the next infusion 
must start with the lead-in doses appropriate for the selected dose level. 
Additional pharmacokinetic data, safety and disease response will be assessed as indicated in the 
flow charts (Section 1.2) and when clinically indicated.  
A Study Committee including the main Investigators, Sponsor’s clinical team, and ad hoc experts, 
when appropriate, will regularly review the safety data, and will make recommendations as 
appropriate. The Study Committee will also decide the RP2D, including the recommended lead-in 
dose and schedule, for the Expansion Part in R/R AML and HR-MDS patients. 
Additional (optional) cohort(s) beyond DL8, or intermediate dose levels, may be evaluated; the 
decision to proceed with these optional cohort(s), however, will be discussed with the Study 
Committee and will be based on the available safety, exploratory, and pharmacokinetic data.  
It is anticipated that the number of patients enrolled in the Dose Escalation Part will be 30 to 40. 
6.3 
MAXIMUM ADMINISTERED DOSE / MAXIMUM TOLERATED DOSE  
The dose escalation will end when the MAD is reached, which will be defined as the dose at 
which ≥33% of evaluable patients have experienced an IMP-related DLT during the 
DLT observation period in a cohort of 6 patients.  
The MTD will be defined as the highest dose level at which no more than 1 patient of a maximum 
of 6 patients experienced an IMP-related DLT.  
The patient population evaluable for MTD determination in the Dose Escalation Part will consist 
of all patients who receive at least 5 out of 6 weekly IV administrations of SAR440234 in DL1 
and DL2, patients who receive at least 6 out of 7 IV administrations of SAR440234 in DL ≥3, and 
patients who discontinue the IMP before completion of Cycle 1 because of a DLT. 
A patient who discontinues the IMP before the end of the DLT observation period or does not 
receive the planned dose for any reason other than DLT, will be replaced by enrolling another 
patient. The first 3 patients treated during the Dose Escalation Part of TED15138 will be replaced. 
Another 3 patients will be enrolled in DL1 and the trial will proceed according to the 3+3 design. 
The dose level below the MAD will be considered the preliminary MTD, providing DLTs are 
observed in fewer than 2 of 6 treated patients (or fewer than one-third if more than 6 patients) at 
that dose level. Intermediate dose levels may be evaluated according to Study Committee 
recommendations. The MTD is generally the highest dose level at which at most 1 patient of a 
dose level cohort experiences a DLT.  
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Although the dose escalation process is guided by the safety evaluation during the DLT 
observation period, cumulative or irreversible toxicities observed in subsequent administrations 
should also be considered for the dose escalation and dose selection decisions (ie, smaller 
increases in dose, expansion of a given dose level, or an intermediate dose level), upon agreement 
between the participant Investigators and the Sponsor. 
In the absence of an MTD, pharmacokinetic and pharmacodynamic parameters may help to define 
the recommended dose of SAR440234 to be tested in the expansion cohort part of the study. 
6.4 
RETREATMENT OF PATIENTS  
Patients may continue treatment with the IMP as long as clinical benefit is possible, or until 
disease progression, unacceptable adverse reaction, patient’s decision to stop the treatment, or 
other reason for discontinuation (Section 6.8.1). Details of the criteria to be followed for 
retreatment of patients following an AE or an interruption in treatment are provided in 
Section 6.5. 
6.5 
DOSE DELAYS/MODIFICATIONS  
Whenever possible, treatment should be performed on the scheduled days. Doses to be given are 
those planned unless a dose modification is warranted due to AE. Dose delays, omissions and 
modifications in response to AEs are delineated in (Section 6.5.3 to Section 6.5.5) and 
summarized in Table 5 (infusion-related reactions), Table 6 (CRS), Table 7 (hematological AEs), 
Table 8 (bone marrow hypocellularity Grade 4), and Table 9 (other AEs). The reasons for dose 
delays or modifications should be documented.  
6.5.1 Dose delays  
If any infusion (excluding Day 4 infusion) cannot be made on the scheduled day, a time 
window of +1 or -1 day is allowed. Subsequent infusions should be administered according to 
the regular weekly schedule.  
Dose delay of ≥3 days: If the infusion is administered ≥3 days later than planned, dosing must 
restart with the lead-in dose (Table 4).  
If a Day 4 infusion cannot be made on the scheduled day: The infusion will be made on the 
next possible day, keeping a 4-day interval before the next infusion. If the infusion cannot be 
administered within 10 days of the last infusion, dosing must restart with the lead-in dose 
(Table 4). 
6.5.2 Dose modifications  
When more than 1 AE is present, treatment modifications will be in accordance with the 
guidelines for the most severe AE. 
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Dose modifications, if required, will be a reduction of 1 step (Table 4) from the last administered 
dose. For example, if the last administered dose was 
 (Step 5), a 1 step dose reduction 
would be to 
 (Step 4). Otherwise, the lead-in dose will be based on the last administered 
dose. 
Table 4 - Definition of dose steps  
Step 
Target Dose 
(ng/kg) 
Lead-in Dosing When Restarting Treatment (if Applicable) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
IV=intravenous 
The target dose is the dose that will be given every 7 days after lead-in dosing. When there is a 
dose delay of 2 days (ie, <10 days from the last infusion), the dose may be given without the 
lead-in dose.  
If there is a dose delay of ≥3 days (ie, the interval after the last infusion is >10 days) due to an AE, 
the dose should be reduced and the lead-in dose for the appropriate step should be administered 
before administering the reduced dose. For example, a 1-step dose reduction from 
 to 
 would require the lead-in doses for 
. According to the scheme in Table 4, 
dosing would commence as follows: 
 on 
Day 8, followed by the planned dose of 
 IV on Day 15 and every 7 days thereafter. 
If an AE requiring dose reduction and lead-in dosing occurs following the 
 dose, the 
1 ng/kg weekly dose will be administered.  
If an AE requiring dose reduction occurs following the 
 dose, the IMP will be 
discontinued. 
After a safe and effective dose has been defined, individual patients who are still on study 
treatment at a different dose may be considered for treatment at another dose or schedule from 
which they were originally assigned, if this dose and schedule is thought to be safer and/or more 
effective, and the Sponsor and Investigator agree that it would be beneficial for the patient. If the 
dose exceeds the originally assigned dose, lead-in dosing will be administered. 
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6.5.3 Dose delay/modification for cytokine release syndrome and infusion-related 
reactions  
Infusion-related reactions and CRS will be graded according to the 2014 NCI Consensus 
Guidelines (Appendix H). Recovery is defined as resolution to Grade 1 or less. CRS-like 
symptoms or signs that occur during infusion will be referred to as infusion-related reactions, 
while CRS-symptoms or signs that develop or persist after the infusion ends will be referred to as 
CRS. The patient’s temperature, heart rate, blood pressure, oxygen saturation, and respiratory rate 
will be assessed every 30 minutes during the infusion. If clinical signs of an infusion-related 
reaction Grade 1 develop, the infusion will be interrupted, and the patient will be treated with 
acetaminophen, diphenhydramine, and ranitidine, or similar agents. If the reaction remains at 
Grade 1 or less, the infusion will resume at 50% of the previous rate after up to 60 minutes of 
interruption. Up-titration of the rate may be attempted according to Section 8.1.2, provided that 
the AE remains Grade ≤1. If more than 60 minutes of interruption are required, the AE will be 
treated as for a Grade 2 infusion-related reaction.  
If the infusion-related reaction is Grade ≥2, interrupt the infusion and treat the reaction. For 
Grade 2 infusion reactions, if the AE improves to Grade 1 or less within 48 hours, retreatment will 
be reattempted on the next scheduled day without a dose escalation, following premedication with 
dexamethasone, montelukast, acetaminophen, diphenhydramine, and ranitidine, or similar agents. 
If tolerated well, dose escalation (if planned) may resume with the next dose. If the 
infusion-related reaction persists for >48 hours, it will be managed as for a Grade 3 infusion-
related reaction. 
For Grade 3 or Grade 4 infusion-related reactions, interrupt the infusion and treat the reaction. 
The next dose will be omitted. After the AE resolves, treatment will restart on the next subsequent 
scheduled dosing day with additional premedication. Dose reduction by 1 step must be applied 
(Table 4). Treatment will restart with the lead-in dose. 
For CRS Grade 1, no dose modifications or delays are required. 
For CRS Grade 2 that resolves within 48 hours, the next dose should be given on schedule, but 
without a dose escalation. For CRS Grade 2 that persists for >48 hours or is present 
<48 hours before the next dose is scheduled, or a first episode of CRS Grade 3, the next dose 
will be omitted. After resolution of the AE, treatment will resume with the lead-in dose and a 
1-step dose reduction. For CRS Grade 3 that fails to resolve to <Grade 1 within 72 hours, 
SAR440234 will be permanently discontinued. For a second or subsequent episode of CRS Grade 
3, SAR440234 will be permanently discontinued. If CRS Grade >2 persists for >14 days after the 
last infusion, SAR440234 will be permanently discontinued. 
For CRS Grade 4, the SAR440234 infusion must be stopped; no re-start is allowed. Treatment 
must be permanently discontinued.  
Guidelines for the resumption of treatment and dose modification following treatment 
interruptions are provided in Table 5 (secondary to infusion-related reactions) and Table 6 
(secondary to CRS). 
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Table 5 - Recommendations for resumption of treatment and dose modification following 
infusion-related reactions during SAR440234 infusion  
Gradea 
During SAR440234 Infusion 
(Infusion-related reaction) 
1 
Interrupt infusion and treat reaction, then resume the SAR440234 infusion at 50% of the rate 
previously achieved, and increase per Section 8.1.2, provided the event remains at Grade 1 or 
below. If AE requires interruption for >1 hour, treat as for Grade 2 event. 
2 
Interrupt infusion and treat reaction, then administer next dose on the next scheduled day without a 
dose escalation, but with additional premedication, provided AE has resolved within 48 hours. If 
tolerated well, dose escalation (if planned) may resume with subsequent doses. 
If AE persists for >48 hours, treat as for Grade 3 event. 
3 or 4 
Interrupt infusion and treat reaction. Omit next dose. 
After AE resolved, restart treatment on the next scheduled dosing day with additional 
premedication. Dose reduction by 1 step must be applied (Table 4). Treatment will restart with the 
lead-in dose. 
The reaction is a DLT if CRS occurs during Cycle 1. 
a Grade of CRS according to the 2014 National Cancer Institute Consensus Guidelines (Appendix H) 
AE=adverse event, DLT=dose-limiting toxicity 
Table 6 - Recommendations for resumption of treatment and dose modification following cytokine 
release syndrome after SAR440234 infusion is completed  
Gradea 
After SAR440234 Infusion completed 
Duration of event <48 hours and event 
resolved >48 hours before next dose is due 
Duration of event >48 hours and/or persistent 
<48 hours before next dose is due 
1 
Administer the next dose when planned and escalate the dose (if planned). 
2 
Administer the next dose when planned, but do 
not escalate next dose. If tolerated well, dose 
escalation may resume subsequently. 
Omit next dose. 
After AE resolved, restart treatment. Dose 
reduction by 1 step must be applied (Table 4). 
Treatment will restart with the lead-in dose. 
The reaction is a DLT if CRS occurs during 
Cycle 1. 
If CRS Grade >2 persists for >14 days after the 
last infusion, SAR440234 will be permanently 
discontinued. 
3  
Omit next dose.  
After AE resolved, restart treatment. Dose reduction by 1 step must be applied (Table 4). Treatment will 
restart with the lead-in dose. Do not escalate past the target dose. 
The reaction is a DLT if CRS occurs during Cycle 1 
If it fails to resolve to Grade ≤ 1 within 72 hours or if it recurs again, treatment will be permanently 
discontinued 
4 
Permanent discontinuation. 
a Grade of CRS according to the 2014 National Cancer Institute Consensus Guidelines (Appendix H) 
AE=adverse event, CRS=cytokine release syndrome, DLT=dose-limiting toxicity 
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6.5.4 Dose delay/modification for hematological adverse events due to SAR440234  
If a patient experiences hematologic AEs (e.g. decreased neutrophil count, decreased platelet 
count, febrile neutropenia, or anemia) related to the underlying hematologic malignancy or 
baseline cytopenias and the investigator and Sponsor agree that continuing treatment is safe, the 
patient will continue treatment with SAR440234 without dose delay and/or modification. 
If the AE does not appear to be related to the underlying hematologic malignancy or baseline 
cytopenias, dose delay and/or modification must be applied as in the following. 
Decreased neutrophil count Grade 4, decreased platelet count Grade 4, or febrile 
neutropenia Grade 3 and Grade 4, and anemia Grade 4: 
 If the AE resolves before the time of the next schedule infusion or within ≤10 days after 
the last infusion, treatment will be given as planned after recovery with dose reduction by 
1 step. 
 If the AE resolves in 10 to 14 days after the last infusion, omit 1 dose. After recovery, 
treatment will resume with dose reduction by 1 step, and will restart with the lead-in dose. 
 If the AE persists >14 days after the last infusion, a bone marrow aspirate will be 
performed. 
- 
If <3 infusions of SAR440234 have been administered, the study treatment will be 
permanently discontinued, 
- 
If ≥3 infusions of SAR440234 have already been administered, the patient will resume 
the study treatment, once the AE has resolved, if there is perceived benefit, and the 
Investigator and Sponsor agree. Dose reduction by 1 step must be applied, and 
treatment will resume with the lead-in dose. 
Bone marrow hypocellularity Grade 4 for at least 14 days 
 The infusion(s) must be omitted until recovery of hypocellularity to baseline or Grade ≤1 
and will be documented by a bone marrow aspirate. 
 If bone marrow hypocellularity resolves in ≤21 days after the last infusion (ie, 2 doses 
omitted), treatment will resume with dose reduction by 1 step, and will resume with the 
lead-in dose. 
 If bone marrow hypocellularity persists for >21 days after the last infusion, the following 
guidelines apply: 
- 
If <3 infusions of SAR440234 have been administered, the study treatment will be 
discontinued permanently, 
- 
If ≥3 infusions of SAR440234 have already been administered, the patient will resume 
the study treatment, once the AE has resolved, if there is evidence of clinical benefit, 
and the Investigator and Sponsor agree. Dose reduction by 1 step must be applied, and 
treatment will resume with the lead-in dose. 
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Guidelines for the resumption of treatment following treatment interruption secondary to 
hematological AEs are summarized in Table 7 and Table 8. 
Table 7 - Dose delays and modifications for hematological adverse events  
Adverse Event 
Condition to 
Continue 
Treatment 
Duration of Adverse Event 
Resolved in 
≤10 days after 
last infusion 
Resolved in 11 
to 14 days after 
last infusion 
Persists >14 days after 
last infusion 
Grade 4 decreased 
neutrophil count 
Grade 4 decreased 
platelet count 
Grade 3 or Grade 4 
febrile neutropenia  
Grade 4 anemia 
Recovery to 
Baseline or 
Grade ≤1 
Administer as planned 
after recovery. Dose 
reduction by 1 step. 
Omit 1 dose. After AE 
resolved, restart 
treatment. Dose 
reduction by 1 step 
and restart treatment 
with the lead-in dose. 
Do not escalate past 
the target dose. 
If <3 infusions administered 
before onset of AE, then 
permanent discontinuationa 
If ≥3 infusions administered 
before onset of AE, then 
resume when AE has 
resolved, if there is evidence of 
clinical benefit. Dose reduction 
by 1 step and restart treatment 
with the lead-in dose. 
a If permanent discontinuation is mandated but there is evidence of clinical benefit and the AE has resolved, study treatment may continue if 
the Investigator and the Sponsor agree 
AE=adverse event 
Table 8 - Dose delays and modifications for bone marrow hypocellularity Grade 4  
Adverse Event 
Condition to 
Continue 
Treatment 
Duration of Adverse Event 
Resolved in ≤21 days after 
last infusion 
Persists >21 days after last 
infusion 
Grade 4 bone 
marrow 
hypocellularity 
Recovery to 
Baseline or 
Grade ≤1 
Omit doses until recovery. Dose 
reduction by 1 step and restart 
treatment with the lead-in dose. Do not 
escalate past the target dose. 
If <3 infusions administered before 
onset of AE, then permanent 
discontinuationa 
If ≥3 infusions administered before 
onset of AE: omit 1 dose. Restart 
treatment when AE has resolved, if 
there is evidence of clinical benefit. 
Dose reduction by 1 step and restart 
treatment with the lead-in dose. 
a If permanent discontinuation is mandated but there is evidence of clinical benefit and the AE has resolved, study treatment may continue if 
the Investigator and the Sponsor agree 
AE=adverse event 
6.5.5 Dose delay/modification for other adverse events not including hematological 
adverse events or cytokine release syndrome due to SAR440234  
Resolution of an AE requires recovery to baseline or Grade ≤1.  
If the AE is related to the underlying hematologic malignancy or baseline cytopenias and the 
investigator and Sponsor agree that continuing treatment is safe, the patient will continue 
treatment with SAR440234 without dose delay and/or modification. 
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If the AE does not appear to be related to the underlying hematologic malignancy or baseline 
cytopenias, dose delay and/or modification must be applied as in the following. 
For patients with AEs that are not hematological and/or not CRS or infusion-related reactions, the 
administration of SAR440234 should be modified as follows: 
Grade 1: 
 Continue treatment as planned. 
Grade 2:  
 If the AE is resolved before the time of the next scheduled infusion, or within ≤10 days 
after the last infusion, treatment will continue without change after recovery. 
 If the AE is resolved >10 days after the last infusion, omit 1 dose. After recovery, 
treatment will restart with the lead-in dose (Section 6.5.2) as appropriate to achieve the 
same step that was administered prior to the onset of the AE. 
 If the patient experiences a third episode of the same AE, the study treatment will be 
permanently discontinued. 
Grade 3: 
 If the AE is resolved before the time of the next scheduled infusion, or within ≤10 days 
after the last infusion, treatment will be continued with a dose reduction of 1 step 
(Section 6.5.2) after recovery. 
 If the AE is resolved in 10 to 14 days after the last infusion, omit 1 dose. After recovery, 
treatment will resume with dose reduction by 1 step. Treatment will restart with the lead-in 
dose. 
 If the AE is not resolved in ≤14 days after the last infusion, treatment will be permanently 
discontinued. 
 If the patient experiences a second episode of the same AE, the study treatment will be 
permanently discontinued. 
Grade 4:  
 The next infusion will be omitted. 
 If the AE resolves in ≤14 days after the last infusion, if there is perceived benefit, and the 
Investigator and Sponsor agree, treatment will restart with the lead-in dose. Dose reduction 
by 1 step will be applied. 
 If the AE is not resolved in ≤14 days after the last infusion, treatment will be permanently 
discontinued. 
 If the patient experiences a second episode of the same AE, the study treatment will be 
permanently discontinued. 
Guidelines for the resumption of treatment following treatment interruption secondary to AEs 
other than hematological AEs, CRS, or infusion-related reactions are provided in Table 9. 
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Table 9 - Dose delay and dose modification for adverse events not including hematological adverse 
events, cytokine release syndrome, or infusion-related reactions  
Grade 
Condition 
to Continue 
Treatment 
Duration of adverse event 
Second 
Episode 
Third 
Episode 
Resolved in 
<10 days after 
last infusion 
Resolved in 
10 to 14 days 
after last 
infusion 
Persisting 
>14 days after 
last infusion 
1 
Not applicable 
No change 
No change 
No change 
2 
Recovery to 
Baseline or 
Grade ≤1 
Administer as 
planned on 
recovery with 
dose as planned. 
Omit 1 dose 
Restart after AE 
resolved.  
Treatment will 
restart with the 
lead-in dose. May 
escalate to planned 
dose level. 
Omit 1 dose. 
Restart after AE 
resolved.  
Treatment will 
restart with the 
lead-in dose. May 
escalate to 
planned dose 
level. 
Allowed. 
Same 
recommend-
ation as for 
first episode. 
Permanent 
discontinua-
tiona 
3 
Recovery to 
Baseline or 
Grade ≤1 
Administer as 
planned on 
recovery. Dose 
reduction by 
1 step. 
Omit 1 dose. 
Restart after AE 
resolved.  
Dose reduction by 
1 step and 
treatment will 
restart with the 
lead-in dose. Do 
not escalate past 
target dose. 
Permanent 
discontinuationa 
Permanent 
discontinua-
tiona 
Not 
applicable 
4 
Recovery to 
Baseline or 
Grade ≤1 
Omit 1 dose. 
Restart after AE resolved if evidence of 
clinical benefit. Treatment restart will be 
with dose reduction by 1 step and with 
the lead-in dose. Do not escalate past 
target dose. 
Permanent 
discontinuationa 
Permanent 
discontinua-
tiona 
Not 
applicable 
a If permanent discontinuation is mandated but there is evidence of clinical benefit and the AE has resolved, study treatment may continue if 
the Investigator and the Sponsor agree 
AE=adverse event 
6.6 
EXPANSION COHORT TO CONFIRM THE MTD  
Approximately 37 patients will be treated at the RP2D of SAR440234 to collect safety, 
pharmacokinetic, pharmacodynamic, and preliminary efficacy data. Patients treated at the RP2D 
in the Dose Escalation Part (except B-ALL patients) together with the patients treated in the 
Expansion Part to a total of the first 17 patients treated at the RP2D (Stage 1 Phase 2), will be 
included in the efficacy analysis. 
Additional or unexpected toxicities will also be explored using all the data gathered during the 
study course (not only at the RP2D). The occurrence of cumulative toxicity, and toxicities 
meeting the DLT criteria observed after the DLT observation period, if any, will also be assessed. 
The preliminary antitumoral activity (ie, tumor response) of the drug will be evaluated according 
to the IWG 2003 recommendations for AML (19) and the revised 2000 criteria for HR-MDS (34), 
and the 2016 NCCN Guidelines for ALL (Appendix D, Appendix F, and Appendix G). 
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6.7 
GUIDELINES FOR MANAGEMENT OF ADVERSE EVENTS  
6.7.1 Recommendations for management of Cytokine Release Syndrome  
SAR440234 will be administered by IV infusion in cycles of 42 days, with weekly administration 
of IMP (except for Cycle 1 Week 1 in DL ≥3 when 2 administrations will be given). Before the 
start of each infusion, the following evaluation must be made: blood pressure, heart rate, oxygen 
saturation, respiration rate, and body temperature. Blood chemistry and complete blood count 
with differential must be obtained <8 hours before starting the SAR440234 infusion and should be 
within the range prescribed in the inclusion criteria (Section 7.2) and exclusion criteria  
(Section 7.3). 
Dexamethasone 20 mg IV will be administered as premedication 4 hours and 1 hour prior to each 
initial IMP administration.  
Montelukast 10 mg oral (PO) will be given once, 4 hours before the start of SAR440234 infusion. 
Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has 
occurred in a previous patient or previous administration in the same patient. This rule will be 
applied for the same patient who experiences a CRS event for subsequent infusions and for all 
patients subsequently enrolled at that dose level or higher. 
If CRS occurs, it will be graded according to the 2014 NCI Consensus Guidelines (Table 10) and 
will be managed as described in Table 11 (31). Patients may require high dose vasopressors, as 
described in Table 12. Guidelines for when and if a patient may resume treatment with 
SAR440234 if CRS or an infusion-related reaction develops during or after an infusion of 
SAR440234 are provided in Table 5 and Table 6 (Section 6.5). 
Table 10 - Grading of cytokine release syndrome according to 2014 National Cancer Institute 
Consensus Guidelines  
Grade 
Definition 
1 
Symptoms are not life-threatening and require symptomatic treatment only; eg, fever, nausea, fatigue, headache, 
myalgias, malaise 
2 
Symptoms require and respond to moderate intervention 
Oxygen requirement <40% fraction of inhaled oxygen or hypotension responsive to fluids or low-dose pressors or 
Grade 2 organ toxicity 
3 
Symptoms require and respond to aggressive intervention 
Oxygen requirement <40% fraction of inhaled oxygen or hypotension requiring high-dose or multiple pressors or 
Grade 3 organ toxicity or Grade 4 transaminitis 
4 
Life-threatening symptoms 
Requirement for ventilator support or Grade 4 organ toxicity (excluding transaminitis) 
5 
Death 
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Table 11 - Evaluation and management of cytokine release syndrome  
Grade 
Evaluation 
Treatment 
1 
Monitoring at least every 30 minutes: 
 
BP, HR, temperature, respiratory rate, oxygen 
saturation. 
 
Symptom assessment. 
Symptomatic treatment with acetaminophen and/or 
antihistamine, if needed 
2 
As for Grade 1, with addition of the following: 
Continuous monitoring of: 
 
BP. 
 
Oxygen saturation. 
 
HR. 
Monitoring at least every 8 hours, or more 
frequently if needed, of: 
 
PaO2. 
 
ECG. 
 
Blood chemistry. 
As for Grade 1, with addition of the following: 
 
Mandatory transfer of the patient to ICU. 
 
IV 
fluid 
resuscitation 
and 
institution 
of 
vasopressors. 
 
Supplemental oxygen. 
 
Start tocilizumab: 
- 
8 mg/kg IV once for patients weighing ≥30 kg, 
- 
12 mg/kg IV once for patients weighing <30 kg, 
- 
If insufficient improvement in CRS within 
12 hours, repeat tocilizumab at the same dose 
every 12 hours for a total of 3 doses. 
3 
As for Grade 2, with the addition of 
echocardiography if there is concern for cardiac 
dysfunction. 
As for Grade 2, with addition of the following: 
 
High-dose or multiple vasopressors Table 12 to 
treat hypotension or poor perfusion. 
 
If no improvement in CRS within 24 hours, start 
dexamethasone 10 mg IV every 6 hours. 
4 
As for Grade 3. 
 
As for Grade 3, with the addition of mechanical 
ventilation if required. 
BP=blood pressure, CRS=cytokine release syndrome, ECG=electrocardiogram, HR=heart rate, ICU=intensive care unit, 
IV=intravenous, PaO2=partial pressure of oxygen in arterial blood 
NOTE: Grading of CRS is based according to 2014 National Cancer Institute Consensus Guidelines (see Table 10). 
For each patient treated, the hospital must have an available bed in the intensive care unit (ICU) in 
case the patient develops hemodynamic or respiratory compromise. The ICU should be staffed by 
a critical care physician who has experience in treating CRS. In addition, the ICU must have the 
necessary equipment to commence immediate treatment and monitoring of a patient with CRS 
Grade ≥2 before he/she is admitted to ICU. Vital signs monitoring shall be made continuously if 
CRS Grade ≥2 develops. 
High dose vasopressors are described in Table 12. 
Table 12 - High dose vasopressors  
Vasopressor 
Dose 
Norepinephrine monotherapy 
≥20 mg/min 
Dopamine monotherapy 
≥10 mg/kg/min 
Phenylephrine monotherapy 
≥200 mg/min 
Epinephrine monotherapy 
≥10 mg/min 
If on vasopressin 
Vasopressin + norepinephrine equivalent of ≥10 mg/min 
If on combination vasopressors 
(not vasopressin) 
Norepinephrine equivalent to ≥20 mg/min 
All doses are required for ≥3 hours 
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Dexamethasone, vasopressors, and oxygen must be tapered quickly after resolution of CRS. 
Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has 
occurred in a previous patient or previous administration in the same patient. This rule will be 
applied for the same patient who experienced a CRS event for subsequent infusions and for all 
patients subsequently enrolled at that dose level or higher. 
Symptomatic treatment and/or pre-medication may include: diphenhydramine 25 to 50 mg IV 
(or equivalent), ranitidine 50 mg IV (or equivalent), and acetaminophen 650 to 1000 mg PO 15 to 
30 minutes (but no longer than 60 minutes) prior to infusion, or during infusion at the 
Investigator’s discretion. 
For patients with CRS Grade ≥2, tocilizumab will be administered at 8 mg/kg infused over 1 hour 
for patients weighing ≥30 kg (maximum dose 800 mg) or 12 mg/kg infused over 1 hour for 
patients weighing <30 kg. Another 8 mg/kg or 12 mg/kg dose IV may be administered in patients 
weighing ≥30 kg (maximum dose 800 mg) or 12 mg/kg for patients weighing <30 kg, 
respectively, if there is insufficient clinical improvement 12 to 24 hours after the first dose. Up to 
3 doses of tocilizumab may be given. 
6.7.2 Tumor Lysis Syndrome (TLS)  
Blood chemistry (creatinine, potassium, calcium, magnesium, phosphorus, and uric acid) will be 
monitored every 8 hours for 72 hours after start of infusion to monitor for tumor lysis. If it occurs, 
appropriate treatment will be initiated that will include correction of serum calcium, potassium, or 
phosphorus abnormalities, and treatment of hyperuricemia with allopurinol and/or rasburicase, as 
indicated in Appendix J (35). 
6.7.3 Hematological adverse events  
Patients will receive packed red blood cells and platelet transfusions to manage anemia and 
thrombocytopenia, if needed. In addition, G-CSF may be administered to patients with 
neutropenia, except in Cycle 1 of the Dose Escalation Part. Antibiotics will be provided to 
patients with febrile neutropenia, in accordance with local practice. Details on the management of 
hematological toxicity are provided in Section 6.5.4. 
6.7.4 Other adverse events  
Other toxicities must be managed as clinically indicated. Details on dose delay and modification 
of dosing for patients with other toxicities are provided in Section 6.5.5. 
6.7.5 Initiation of a new cycle of therapy  
In the Dose Escalation Part, at the end of Cycle 1, 43 days after the first SAR440234 infusion, a 
patient may begin Cycle 2 if he or she did not experience a DLT. Details on the start of the next 
infusions are provided in Section 6.5. 
In the Dose Escalation Part Cycle 2 and beyond, and for the Expansion Part Cycle 1 and beyond, 
details on the start of the next infusions are provided in Section 6.5. 
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6.8 
DURATION OF STUDY PARTICIPATION  
6.8.1 Duration of study participation for each patient  
The duration of the study for a patient will include a period for screening of up to 14 days starting 
from the time the patient signs the informed consent form. The cycle duration is 42 days with 
weekly IMP administration (except for Cycle 1 Week 1 in DL ≥3 when 2 administrations will be 
given). After study treatment discontinuation, patients will return to the study site 30 days after 
the last IMP administration for end of treatment assessments. If a patient discontinues 
SAR440234 prior to day 42, the day 42 evaluation must be performed on the day that the decision 
is made that the patient will not continue treatment with SAR440234. EOT evaluation for a 
patient must be performed within 30 days of the last administration of SAR440234 received by 
the patient. If a patient does not plan to return to the study site for an EOT visit, the EOT 
evaluation must be performed on the day that the decision is made that the patient will not 
continue treatment with SAR440234. 
Patients may continue treatment with the IMP as long as clinical benefit is possible, or until 
disease progression, unacceptable adverse reaction, patient’s decision to stop treatment, or other 
reason for discontinuation. During the follow-up period, IMP-related AEs and all serious adverse 
events (SAEs) (regardless of relationship to study treatment) present at the time of study treatment 
discontinuation will be followed every month until resolution or stabilization, or until initiation of 
another antineoplastic therapy. If a patient is unable to attend monthly follow-up visits, the 
investigator will obtain follow up information via telephone call and record review from the 
treating physicians. 
Clinical benefit is defined as: CR, CRi, PR, reduction of blast count, stabilization of symptoms 
and conditions, or any other clinical benefit identified and documented by the Investigator. 
Patients without documented disease progression at the end of a treatment visit who have not yet 
started treatment with another anti-cancer therapy will proceed with monthly follow-up visits until 
initiation of another anti-cancer therapy, disease progression, study cut-off date, or death, 
whichever comes first. If a patient is unable to attend monthly follow-up visits, the investigator 
will obtain follow up information via telephone call and record review from the treating 
physicians. 
The first cut-off date will be at the end of the first cycle of the last patient treated in the 
Dose Escalation Part in order to have at least the first cycle evaluable for all patients for 
determination of the MTD and for the RP2D. 
The second cut-off date will be when the last patient in the Expansion Part will have been treated 
for 2 cycles (approximately 3 months), or has early progression, whichever occurs first, in order to 
assess tumor response. After the second cut-off date, ongoing patients will receive study treatment 
until disease progression or occurrence of an AE leading to treatment discontinuation, whichever 
is earlier, and they will only be followed for study treatment administration, SAEs, study 
treatment-related AEs, and reason for end of treatment. 
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6.8.2 Determination of end of clinical trial (all patients)  
The clinical trial will end 30 days after the last IMP administration. 
6.9 
INTERIM ANALYSIS  
An interim analysis is planned after the first 17 patients of the Expansion Part. Refer to 
Section 13.5 for details on interim analysis.  
6.10 
STUDY COMMITTEES  
The Study Committee will include the Principal Investigator or delegate at each site, clinical team 
members from the Sponsor, and independent ad hoc experts, when appropriate. The Study 
Committee will review clinical data, including SAEs, adverse events of special interest (AESIs), 
DLTs, and deaths, on a regular basis. The Study Committee will decide whether or not to escalate 
to the next dose level based on their knowledge of the whole safety profile and on the design of 
the study. The Study Committee will also make recommendations on the choice of the RP2D. 
Decisions regarding patient treatment and cohort expansion will be discussed and will be clearly 
documented in the discussion minutes. 
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7 
SELECTION OF PATIENTS  
7.1 
NUMBER OF PATIENTS  
It is anticipated that approximately 72 patients (67 to 77 patients) will be enrolled in this study: 
30 to 40 patients in the Dose Escalation Part and 37 patients in the Expansion Part (Section 13.1). 
7.2 
INCLUSION CRITERIA  
I 01. Confirmed diagnosis of primary or secondary AML (any subtype except acute 
promyelocytic leukemia) according to World Health Organization (WHO) classification or 
MDS with a Revised International Prognostic Scoring System (R-IPSS) risk category of 
intermediate or higher (36) (Appendix E). Patients must have exhausted available 
treatment options and must not be eligible for any treatment known to provide clinical 
benefit. 
I 02. Patients with AML must have relapsed or refractory disease that has been resistant to 
available therapies, as defined by any 1 of the following criteria: 
- 
Leukemia refractory to ≥2 intensive remission induction attempts, 
- 
Leukemia in first relapse within 1 year following allogeneic stem cell transplant, 
- 
Leukemia in second or higher relapse, 
- 
Not eligible for intensive remission induction therapy and have persistent leukemia 
despite ≥2 cycles of therapy, including any of the following: hypomethylating agent 
(eg, decitabine or 5-azacitidine), chemotherapy, or targeted agents (eg, gemtuzumab 
ozogamicin or enasidenib). 
I 03. During the Dose Escalation Part, patients with B-ALL without extramedullary lesions, in 
second or subsequent relapse, could also be recruited at any DL ≥3 during the 
3 +3 escalation period. B-ALL patients should have completed previously ≥1 cycle of a 
salvage regimen, including any of the following: chemotherapy, blinatumomab, tyrosine 
kinase inhibitors, cellular therapy (eg, tisagenlecleucel), or targeted agents (eg, inotuzumab 
ozogamicin). Patients must have exhausted available treatment options and must not be 
eligible for any treatment known to provide clinical benefit.  
I 04. Patients with HR-MDS must have >10% blasts in the bone marrow at the time of 
enrollment and fit one of the following categories: 
- 
Not eligible for induction therapy and having completed ≥2 cycles of therapy, 
including any of the following: hypomethylating agent (eg, 5-azacitidine or 
decitabine), chemotherapy, or targeted agents. 
- 
Not eligible for allogeneic stem cell transplant and having completed ≥1 course of 
induction therapy. 
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I 05. Signed written informed consent. 
7.3 
EXCLUSION CRITERIA  
Patients who have met the above inclusion criteria listed in Section 7.2 for one of R/R AML, 
B-ALL, or HR-MDS, will be screened for the following exclusion criteria:  
E 01. Age <16 years old. 
E 02. Eastern Cooperative Oncology Group (ECOG) performance status >2 (11). 
E 03. Abnormal laboratory parameters, including the following:  
- 
Total bilirubin >1.5 x ULN unless Gilbert’s syndrome is present, 
- 
ALT, AST, or alkaline phosphatase >2.5 x ULN,  
- 
Serum creatinine >2 x ULN and/or creatinine clearance <30 mL/min, 
- 
Grade 4 hematological toxicity: febrile neutropenia, bone marrow hypocellularity, 
symptomatic disseminated intravascular coagulation, life-threatening anemia, or 
life-threatening thrombotic thrombocytopenic purpura, 
- 
White blood cell count > 30,000/mm3.  
- 
If the white blood count exceeds 30,000/mm3, hydroxyurea may be used to reduce 
the white blood cell count to < 30,000/ mm3 at start of treatment. 
- 
Hydroxyurea may be administered to patients at the Investigator’s discretion 
during Cycle 1, but must be stopped ≥1 day prior to Cycle 2, Day 1. 
E 04. Graft-versus-host disease following allogeneic stem cell transplantation requiring 
treatment with more than 10 mg of oral prednisone or equivalent daily. The stem cell 
transplant and/or donor lymphocyte infusion should have been performed more than 
3 months before study treatment start. 
E 05. History of an active or chronic autoimmune condition that has required or requires therapy. 
E 06. Prior treatment with an anti-CD123-directed agent. 
E 07. Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is 
allowed. 
E 08. Previous treatment with chemotherapy, radiotherapy, or immunotherapeutic agents in the 
4 weeks prior to IMP administration (Cycle 1 Day 1), except for hydroxyurea. 
E 09. Previous treatment with any other investigational agent in the 4 weeks prior to IMP 
administration (Cycle 1 Day 1). 
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E 10. Receiving at the time of first IMP administration concurrent steroids >10 mg/day of oral 
prednisone or the equivalent for ≥3 months, except steroid inhaler, nasal spray, or 
ophthalmic solution. 
E 11. Requirement for tocilizumab for any other diagnosis within ≤14 days before the first 
administration of SAR440234. 
E 12. Known contraindication to any of the noninvestigational medicinal products (NIMPs) 
(dexamethasone and tocilizumab), acetaminophen, diphenhydramine, ranitidine, 
montelukast or similar agents. 
E 13. Evidence of active central nervous system leukemia at the time of enrollment. 
E 14. Known acquired immunodeficiency syndrome (AIDS-related illnesses) or HIV disease 
requiring antiretroviral treatment, or having active hepatitis A, B or C infection, or 
tuberculosis. 
E 15. Pregnant and breast-feeding women, female patients of childbearing potential, and male 
patients with female partners of childbearing potential who are not willing to avoid 
pregnancy by using an adequate method of contraception (2 barrier method or 1 barrier 
method with a spermicide, intrauterine device, or hormonal contraception with inhibition 
of ovulation, for 2 weeks prior to the first dose of SAR440234, during treatment, and 
12 weeks after the last dose of study treatment). A woman is considered of childbearing 
potential, ie, fertile, following menarche and until becoming postmenopausal unless 
permanently sterile. 
E 16. Any country-related specific regulation that would prevent the patient from entering the 
study. 
E 17. Any clinically significant, uncontrolled medical conditions that, in the Investigator’s 
opinion, would expose excessive risk to the patient or may interfere with compliance or 
interpretation of the study results. 
E 18. Patients weighing <60 kg (DL1, DL2, and DL3 only). 
Patients who have been withdrawn from the study after the study treatment has started cannot be 
reincluded in the study. Their inclusion and treatment number must not be re-used.  
Rescreening is permitted for patients who have not received treatment in this study.  
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
The IMP is presented as a lyophilisate powder for solution for IV injection at 
 
(CD3-CD123) 
 
8.1.1 Dose of drug per administration  
Starting dose of SAR440234 is described in Section 6.2. 
8.1.2 Preparation, reconstitution, and administration of SAR440234  
Dilution method, calculation of volume to be infused, and administration of SAR440234 are 
detailed in the Pharmacy Manual. 
SAR440234 requires a 
, as detailed in the Pharmacy Manual. Special 
care should be taken to avoid accidental overdose with the medication.  
Infusion-related reactions are expected, thus infusion rates should be gradually increased every 
30 minutes, as tolerated, for each administration. Minimum and maximum infusion rates have also 
been defined for each dose level, as described in the Pharmacy Manual.  
 
  
The infusion rate schedule for SAR440234 is described in the Pharmacy Manual. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
Dexamethasone: 4 mg/mL for IV injection. 
Tocilizumab: 200 mg/10 mL vial for IV injection. 
Montelukast: 10 mg tablet for oral administration. 
Dexamethasone 20 mg IV will be instituted as systematic premedication 4 hours and 1 hour prior 
to each initial IMP administration.  
Montelukast tablets 10 mg will be given orally once, 4 hours before the start of SAR440234 
infusion. 
Dexamethasone 20 mg IV must be repeated 5 hours after the start of infusion if CRS Grade 2 has 
occurred in a previous patient or previous administration in the same patient. This rule will be 
applied for the same patient who experiences a CRS event for subsequent infusions and for all 
patients subsequently enrolled at that dose level or higher. 
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For each patient treated, the clinical site must have at least 2 full doses of tocilizumab in the 
clinical pharmacy ready for immediate administration in case of CRS Grade 2 or above. 
Guidelines for management of patients with CRS are included in Section 6.7. 
For patients with Grade 2 CRS, tocilizumab will be administered at 8 mg/kg infused over 1 hour 
for patients weighing ≥30 kg (maximum dose 800 mg) or 12 mg/kg infused over 1 hour for 
patients weighing <30 kg.  
If there is insufficient improvement in CRS within 12 hours, tocilizumab may be repeated at the 
same dose every 12 hours for a total of 3 doses. The interval between consecutive doses should be 
at least 8 hours. Subcutaneous infusion of tocilizumab is not approved for CRS treatment. 
Tocilizumab must not be used for prophylaxis of CRS. Patients with Grade 3 or Grade 4 CRS 
should be treated with tocilizumab as for patients with Grade 2 CRS. For patients with Grade 3 or 
Grade 4 CRS who do not respond to tocilizumab within 24 hours, dexamethasone 10 mg IV 
should be given every 6 hours.  
For patients weighing ≥30 kg or more, tocilizumab should be diluted in 100 mL of 0.9% or 
0.45% sodium chloride injection USP for IV infusion and administered by drip infusion over 
1 hour. For patients weighing <30 kg, tocilizumab should be diluted in 50 mL of 0.9% or 
0.45% sodium chloride USP for IV infusion and administered by drip infusion over 1 hour. 
Tocilizumab should not be given as a bolus or push. 
8.3 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
SAR440234 will be supplied in boxes of 
. 
Packaging is described in the Pharmacy Manual. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.4 
STORAGE CONDITIONS AND SHELF LIFE  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage), 
and information on in-use stability and instructions for handling the sanofi compound must be 
managed according to the rules provided by the Sponsor. 
SAR440234 must be stored at 
. All vials must be kept in their box 
until use. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
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8.5 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
The IMP will be dispensed in accordance with the Investigator’s prescription, and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP; deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 10.5.7). 
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 will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.5.1 Treatment accountability and compliance  
Administration of the IMP will be supervised by the Investigator or Subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from the Sponsor, 
dispensed for patient, and destroyed or returned to the Sponsor. The packaging batch number 
(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, 
infusion rate, and start and stop times of the drug administration to the patient. 
8.5.2 Return and/or destruction of treatments  
All used and partially used IMP (SAR440234) will be destroyed at the study site after an accurate 
accountability has been performed and signed by the Investigator (or the pharmacist). 
All unused IMP may be destroyed at the site or retrieved by the Sponsor. The Investigator will not 
destroy the unused IMP unless the Sponsor provides written authorization. 
A detailed treatment log form of the destroyed and/or returned IMP will be established with the 
Investigator (or the pharmacist) and countersigned by the Investigator and the Monitoring Team. 
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8.6 
CONCOMITANT TREATMENT  
All treatments being taken by the patient 14 days prior to registration onto the study, or at any 
time during the study in addition to the IMP are regarded as concomitant treatments, and the type, 
dose and route of administration must be documented on the appropriate pages of the eCRF. 
Hydroxyurea may be administered to patients at the Investigator’s discretion during cycle 1 but 
must be stopped >1 day prior to the start of cycle 2. 
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 eCRF: 
 Supportive treatment as medically indicated for the patient’s wellbeing 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 eCRF. 
Details of specific treatments for the management of AEs are provided in Section 6.7. 
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 the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies. 
 Radiotherapy, even if palliative in intent, may not be given during the study. 
 Prophylactic use of hematopoietic growth factors (eg, G-CSF, GM-CSF, erythropoietin) 
during the DLT observation period in the Dose Escalation Part only. 
 Cytokine release may modulate CYP450 enzymes (decrease activity) and cause drug-drug 
interactions by increasing concentrations of drugs primarily metabolized by CYPs. 
Therefore, patients treated or intended to be treated with drugs known to be CYP 
substrates with a narrow therapeutic index (Appendix B) should be carefully monitored for 
toxicity. Cytokine release may also have an impact on transporters. Therefore, patients 
should be monitored closely when treated, or intended to be treated, with transporter 
substrates that have a narrow therapeutic index. These drugs include: digoxin, glyburide, 
and methotrexate. 
8.7 
POST INVESTIGATIONAL MEDICINAL PRODUCT  
The patient’s treatment plan after discontinuation of the IMP will be at the discretion of the 
treating physician. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
SAFETY  
The major purpose of this Phase 1/2A study is to establish, based on DLTs, the MTD of 
SAR440234 administered IV weekly (except for Cycle 1 Week 1 in DL ≥3 when 
2 administrations will be given) to patients with hematologic malignancy (R/R AML, B-ALL, or 
HR-MDS). Safety is thus the primary study endpoint and will be assessed continuously.  
The safety profile will be assessed from the findings of physical examinations (preferably by the 
same physician in each center), laboratory tests, and reports of AEs, etc, and will be based on 
incidence, severity (as graded by the NCI-CTCAE v4.03; except for CRS, which will be graded 
according to the 2014 NCI Consensus Guidelines, Table 10), and cumulative nature of TEAEs 
(defined as AEs that develop or worsen in grade or become serious during the on-treatment 
period). 
9.1.1 Dose-limiting toxicities  
With an objective of defining the RP2D and dose schedule, the safety of SAR440234 will be 
evaluated using the following assessments during the Dose Escalation Part: 
 Incidence of DLT (as defined in Section 6.2.1) observed during the DLT observation 
period (6 IMP administrations). 
 Incidence of allergic reactions/hypersensitivity and CRS/acute infusion reactions. 
Potential and IMP-related DLTs will be considered as AESIs. As such, the Investigators will be 
required to report them to the Sponsor within 24 hours of the Investigator becoming aware of each 
event. The Investigator will attach the DLT-specific CRF page to the transmitted DLT/AESI form 
or will complete the specific DLT form in the electronic case report form (eCRF). 
Potential DLTs are defined as the occurrence of any of the following related to the study therapy 
using NCI-CTCAE v4.03, or the NCI Consensus Guidelines for grading CRS (Table 10), as 
appropriate:  
Hematological abnormalities:  
 Grade 4 hematological toxicities, ie, new onset or worsening of life-threatening 
hematological abnormalities after administration of SAR440234: 
- 
Grade 4 bone marrow hypocellularity, if not caused by disease progression and not 
improved to baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 decreased neutrophils, if not present at baseline and not resolved to baseline 
value or Grade ≤1 within 14 days, 
- 
Grade 4 febrile neutropenia not resolved within 7 days, 
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- 
Grade 4 decreased platelet count, if not present at baseline and not improved to 
baseline value or Grade ≤1 within 14 days, 
- 
Grade 4 anemia, if not improved to baseline value or Grade ≤1 within 14 days. 
Nonhematological abnormalities: 
 Any Grade ≥3 nonhematological AE unless either caused by disease progression or 
obviously unrelated cause or caused by a laboratory abnormality without associated 
clinical consequences that resolves within 5 days. 
 Any TEAE that, in the opinion of the Principal Investigator and Sponsor, is of potential 
clinical significance such that further dose escalation would expose patients to 
unacceptable risk. 
 Grade 3 or Grade 4 CRS. 
 Grade 2 CRS if it persists for >48 hours or is present <48 hours before the time when the 
next planned dose of SAR440234 is due. 
Other: IMP-related adverse reaction leading to a delay or omission of more than 2 weeks 
between 2 planned administrations of SAR440234 due to failure to improve to baseline or 
Grade ≤1. 
At the end of each appropriate cycle (ie, end of Cycle 1), each patient must be assessed by the 
Investigator as to whether or not the patient experienced a DLT. This information must be 
recorded on the appropriate eCRFs, and an electronic DLT notification (either DLT or not) will be 
sent to the Sponsor, before a subsequent cycle may begin. 
The reported potential DLTs will be reviewed by the study committee in order to determine their 
relationship to the IMP. 
9.1.2 Adverse events  
Adverse events will be collected from the signing of the study main informed consent up to 
30 days after the last IMP administration. During the follow-up period, ongoing SAEs regardless 
of relationship to IMP, and ongoing or new study treatment related AEs will be followed until 
resolution or stabilization. Adverse events encountered before the start of SAR440234 treatment 
will be summarized separately. 
Pretreatment AEs, TEAEs, and post-treatment AEs will be graded according to the 
NCI-CTCAE v4.03, or the NCI Consensus Guidelines for grading CRS (Table 10) as appropriate, 
and will be coded to a “Preferred Term” and associated primary “System Organ Class” using the 
version of MedDRA (Medical Dictionary for Regulatory Activities). Adverse events will be 
summarized with respect to the type, frequency, severity, seriousness, and relatedness 
The study-specific and general safety criteria are developed in Section 10. 
9.1.3 Laboratory safety variables  
The schedule for laboratory assessment is described in Study Procedures (Section 12) and 
Study Flowcharts (Section 1.2). 
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9.1.4 Clinical examinations  
The schedule for clinical examinations is described in the Study Procedures (Section 12) and the 
Study Flowcharts (Section 1.2). 
9.1.5 Immunogenicity  
9.1.5.1 Sampling times  
The blood collection time points are defined in the pharmacokinetic/pharmacodynamic flow 
charts (Section 1.3) to measure ADA in plasma and to conduct the immunogenicity analysis. 
The sampling times schedule for ADA detection may be modified (ie, samples omitted) based on 
updated knowledge of SAR440234 potential immunogenicity. Immunogenicity sampling will be 
stopped at the second study cut-off date in all patients. 
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples missed or lost for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. The dates and times of drug administration should also 
be recorded precisely. 
The remaining plasma samples will be kept for other possible exploratory analysis. The results of 
this analysis will not be included in the clinical study report but in a stand-alone report, if 
applicable. 
9.1.5.2 Sample handling procedures  
Detailed instructions for sample preparation and shipping for SAR440234 ADA assay samples 
will be provided to the study sites in a separate Laboratory Manual. 
9.1.5.3 Bioanalytical method  
The bioanalytical methods used for immunogenicity assessment will be performed according to a 
validated method under the responsibility of Sanofi Biomarkers and Clinical Bioanalyses 
Department (Alfortville, France). 
9.1.6 Other safety endpoints  
Safety assessments are described in the Study Procedures (Section 12) and the Study Flowcharts 
(Section 1.2). 
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9.2 
PHARMACOKINETIC EVALUATION  
9.2.1 Sampling times  
The blood collection time points are defined in the pharmacokinetic/pharmacodynamic flow 
charts (Section 1.3) to measure SAR440234 concentrations in plasma and to conduct the 
pharmacokinetic analysis. The sampling times schedule may be modified (ie, samples omitted) 
based on updated knowledge of SAR440234’s pharmacokinetic behavior. Pharmacokinetic 
sampling will be stopped at the second study cut-off date in all patients. 
 It is of utmost importance to collect all blood samples at the specified times and according 
to the specifications. 
 Samples missed or lost, for any reason should be recorded. Actual dates and times of 
blood collection should be recorded in the eCRF. The dates and times of drug 
administration should also be recorded precisely. 
 Remaining plasma samples will be kept for other possible exploratory analysis. Results of 
this analysis will not be included in the clinical study report but in a stand-alone report, if 
applicable. 
9.2.2 Pharmacokinetic sample handling procedure  
Detailed instructions for pharmacokinetic sample preparation will be provided to the study sites in 
a separate Laboratory Manual. 
9.2.3 Bioanalytical method  
The bioanalytical method used for pharmacokinetic assessment will be performed according to a 
validated method under the responsibility of Sanofi Biomarkers and Clinical Bioanalyses 
Department (BCB, Alfortville, France). 
9.2.4 Pharmacokinetic parameters  
The pharmacokinetic analysis will be carried out by Pharmacokinetic, Dynamic & Metabolism 
group (PKDM, Alfortville, France). Pharmacokinetic parameters will be calculated with PKDMS 
software (Pharsight), using noncompartmental methods from SAR440234 plasma concentrations. 
The parameters will include, but may not be limited to those listed in (Table 13). Additionally, a 
modeling approach may be used if deemed relevant and applicable. 
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Table 13 - List of pharmacokinetic parameters and definitions  
Parameters 
Definition 
Ceoi 
Concentration observed at the end of intravenous infusion 
Cmax 
Maximum concentration observed 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of quantification 
tlast 
Time of the last concentration observed above the lower limit of quantification (ie, Clast) 
Ctrough 
Concentration observed just before treatment administration during repeated dosing 
AUClast 
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to 
time of the last concentration observed above the lower limit of quantification (ie, Clast) 
AUC 
Area under the concentration versus time curve calculated using the trapezoidal method from time zero to infinity 
according to: AUC = AUClast + Clast/λz , where λz is the slope of the regression line of the observed terminal phase of 
the concentration versus time curve, in semi-logarithmic scale 
AUC0-T 
Area under the concentration versus time curve calculated using the trapezoidal method during a dosing interval (T) 
9.3 
PHARMACOGENETIC ASSESSMENT  
Not applicable. 
9.4 
SPECIFIC ASSESSMENTS  
9.4.1 Biomarker assessments  
Exploratory endpoints include: 
 Assessment of CD123 expression in cells in the peripheral blood and bone marrow 
aspirate. Percentage of CD123-expressing cells may be a pharmacodynamic biomarker for 
response to the IMP.  
 Monitoring of T-cell subpopulations (eg, CD4, CD8) and activation status in the peripheral 
blood and bone marrow aspirate.  
 Minimal residual disease by molecular biology assessment and/or flow cytometry will be 
assessed at the study sites in bone marrow aspirates from patients achieving a CR or 
CRi and correlated with clinical outcome. 
 Assessment of plasma cytokine levels in blood at specific time points following treatment 
administration to evaluate potential associations of cytokine levels with safety and clinical 
outcomes. 
Specific assessments are described below. Additional analysis, not specified in the protocol but 
related to the drug safety, action and/or effect of SAR440234, may be conducted on remaining 
samples pending evolving literature.  
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9.4.1.1 Cytokine and acute phase protein assessment  
Plasma levels of pro-inflammatory cytokines, including IL-6 and IFN-γ, as well as blood levels of 
2 acute phase proteins, CRP, and ferritin, will be assessed during the trial (Section 1.3). Samples 
will be collected at screening and for those patients who have already entered the trial at predose, 
and during Cycle 1 and Cycle 2. Planned sampling times for cytokine and acute phase protein 
assessment can be found in the pharmacokinetic/immunogenicity flow charts. The sampling times 
schedule for cytokines and acute phase protein assessment may be modified (ie, samples omitted) 
based on updated knowledge during the course of the study. Cytokine analysis will be performed 
in a centralized laboratory (contract research organization [CRO]). CRP and ferritin 
measurements will be performed locally at sites.  
Additional samples for analysis of cytokines and acute phase proteins must be collected in case of 
CRS Grade ≥2 if it occurs, or as soon as it is diagnosed.  
Refer to separate laboratory manual for details concerning handling procedures.  
9.4.1.2 Immunophenotyping by flow cytometry  
Immunophenotyping will be performed on blood and bone marrow samples at screening, and for 
those patients who have already entered the trial as planned in the study flow charts (Section 1.3). 
Analysis will include monitoring of CD123 expression on normal cells, of CD123 expression in 
leukemic cells and kinetics of this expression under treatment and of T-cell subpopulations 
(eg, CD4, CD8), and activation status among other potential subpopulations. Processing of 
samples and analysis will be performed in a centralized laboratory (CRO). Immunophenotyping 
sampling will be stopped at the second study cut-off date in all patients. 
Refer to separate laboratory manual for details concerning handling procedures.  
9.4.1.3 Disease molecular subtype  
Information about disease molecular subtype will be collected at screening. Disease molecular 
subtype could be reassessed locally when clinically indicated.  
9.4.1.4 Minimal residual disease  
The modalities of MRD evaluation should be identified and a baseline level of disease 
involvement should be determined from the Screening bone marrow aspirate. MRD evaluation 
will be performed on the bone marrow if the patient enters CR or CRi. If MRD is positive, the 
MRD assessment will be repeated on subsequent bone marrow evaluations, or as clinically 
indicated. This assessment will be performed locally, if available. 
9.5 
SAMPLED BLOOD VOLUME  
The volume of blood to be collected during the trial and a description of the samples and their 
processing are described in the laboratory manual. 
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9.6 
FUTURE USE OF SAMPLES  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patients who have consented to it, the samples that are unused or left over after 
testing may be used for other research purposes (excluding genetic analysis) related to oncology 
that are defined in the present protocol.  
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioanalytical method, or to identify new drug targets or biomarkers.  
These samples will remain labeled with the same identifiers used during the study (ie, patient ID). 
They will be transferred to a sanofi site (or a subcontractor site) which can be located outside of 
the country where the study is conducted. The Sponsor has included safeguards for protecting 
patient confidentiality and personal data (see Section 16.3 and Section 16.5). 
9.7 
EFFICACY  
In the Expansion Part, disease response for R/R AML and HR-MDS will be an additional primary 
endpoint: 
 Preliminary anti-leukemia and anti-MDS activity as defined by IWG (34): 
- 
Overall response rate (ORR) including CR, CRi, and PR, 
- 
Duration of response, 
- 
Event-free survival. 
9.7.1 Criteria for response (antitumoral activity)  
The IWG and NCCN criteria will be followed, as appropriate, for assessment of response 
(Appendix D, Appendix F, and Appendix G). 
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10 
PATIENT SAFETY  
10.1 
SAFETY ENDPOINTS ASSESSED IN THIS TRIAL  
Refer to Section 9.1 for definition of safety criteria, parameters to be analyzed, and method of 
sample collection. 
10.2 
SAFETY INSTRUCTIONS  
Please refer to Section 6.7. 
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. 
Note: Examples of such events (list is not exhaustive) are intensive treatment in an emergency 
room or at home (for allergic bronchospasm, blood dyscrasias, or convulsions) or asymptomatic 
ALT increase ≥10 ULN that does not result in hospitalization, or development of drug 
dependency or drug abuse. 
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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 eCRF. 
Whenever possible, diagnosis or single syndrome should be reported instead of 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  
In the case of an SAE, an AESI, a pregnancy report, or an overdose, the Investigator or any 
designees must immediately: 
 ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send e-notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
 SEND (preferably by fax or e-mail) the photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team. Care should be taken to ensure that the patient's identity is protected and the 
patient’s identifiers in the clinical trial are properly mentioned on any copy of source 
document provided to the Sponsor. For laboratory results, include the laboratory normal 
ranges. 
 All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medication, patient status) should be sent (by fax or e-mail) to the monitoring team within 
24 hours of knowledge. In addition, any effort should be made to document further each 
SAE that is fatal or life threatening within the week (7 days) following initial notification. 
 A back-up plan is used (using paper flow) when the eCRF system does not work. 
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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 AE 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 nonserious adverse event  
In the case of a treatment discontinuation due to a nonserious AE: 
 ENTER (within 24 hours) the information related to treatment discontinuation due to a 
non-SAE in the appropriate screens of the eCRF (AE with the box “action taken with 
IMP” ticked “permanently discontinued”, together with the end of treatment form with 
reason that should be ticked “AE”); the system will automatically send the notification to 
the monitoring team after approval of the Investigator within the eCRF or after a standard 
delay. 
10.5.5 Adverse event of special interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
SAR440234 program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
Investigational medicinal product related DLTs (as defined in Section 9.1.1) are considered as 
AESIs, and as such, the Investigators will be required to report them to the Sponsor within 
24 hours of the Investigator becoming aware of the event. The Investigator will attach the 
DLT-specific eCRF page to the DLT/AESI form. 
Additional AESIs include the following: 
 Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP: 
- 
Pregnancy in a female patient or in a female partner of a male patient will qualify as an 
SAE only if it fulfills one of the seriousness criteria (see Section 10.4), 
- 
In the event of pregnancy in a female patient, treatment with the IMP should be 
discontinued, 
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined. 
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 Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count) within the intended therapeutic interval, adjusted according to the tested drug 
 Infusion: increase of at least 30% of the dose to be administered in the specified 
duration or if the dose is administered in less than half the recommended duration 
of administration. 
 Oral: increase of at least 30% of the dose to be taken. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
 Other project specific AESIs: 
- 
Cytokine release syndrome. 
10.5.6 Laboratory abnormalities  
Laboratory abnormalities should be monitored, documented, and managed according to the 
related flowchart (see Section 1.2). Laboratory values will be reported in the appropriate pages of 
eCRF. 
Laboratory abnormalities should be reported as AE only in case they lead to an action on study 
treatment or if they are serious (see Section 10.5.1). 
10.5.7 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. Appropriate 
information (eg, samples, labels or documents, eg pictures or photocopies) related to product 
identification and to the potential deficiencies may need to be gathered. The Investigator will 
assess whether or not the quality issue has to be reported together with an AE or SAE. 
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), to the regulatory authorities, institutional ethics 
committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.  
 All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
 The AESIs (eg, DLT, CRS) to those regulatory authorities who require such reporting.  
Adverse events that are considered expected are specified by the reference safety information, ie, 
the Investigator Brochure.  
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  
Pregnancy 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(s) for discontinuation and this should be documented in 
the eCRF. 
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 (patient’s decision to 
stop treatment), or at the request of their legally authorized representative without any 
effect on their care. “Legally authorized representative” is considered to be an individual 
or judicial or other body authorized under applicable law to consent on behalf of a 
prospective patient to the patient’s participation in the procedure(s) involved in the 
research. Withdrawal of consent for treatment should be distinguished from withdrawal of 
consent for follow-up visits and from withdrawal of consent for nonpatient contact 
follow-up, eg, medical records check. The value of all their study data collected during 
their continued involvement will be emphasized as important to the public health value of 
the study. Patients who withdraw should be explicitly asked about the contribution of 
possible AEs to their decision to withdraw consent. AE information elicited should be 
documented. Preferably the patient should withdraw consent in writing and, if the patient 
or the patient’s representative refuses or is physically unavailable, the site should 
document any case of withdrawal of consent. 
 If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s wellbeing. These situations include the following: 
- 
Disease progression, 
- 
Unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment, 
- 
Requirement for radiotherapy, even if palliative in intent. 
 Patient is lost to follow-up. 
If patients are clinically stable, possibly deriving clinical benefit from therapy, and tolerating the 
treatment well, the patient may continue on treatment. 
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11.1.2 Handling of patients after permanent treatment discontinuation  
All permanent treatment discontinuation must be recorded by the Investigator in the appropriate 
screen of eCRF when considered as telephone call and record review if the patient is unable to 
attend monthly post-study visits. After study treatment is discontinued, patients must complete a 
visit within 30 days after the last administration of the IMP, as described in Section 12.7. If a 
patient does not plan to return for an EOT visit, the EOT evaluation must be performed on the day 
that the decision is made that the patient will not continue SAR440234. Post-study follow up must 
be performed by telephone call and record review if the patient is unable to attend monthly post-
study visits. 
Patients who have been withdrawn from the study treatment cannot be re-entered into the study. 
Patients will be followed up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be followed up 
as specified in this protocol, whichever comes last. 
If possible, after permanent discontinuation of treatment, patients will be assessed using the 
procedure normally planned for the last dosing day with the IMP. 
11.2 
REPLACEMENT OF PATIENTS  
During the Dose Escalation Part of the study, any patient who is not evaluable for DLT, ie, who 
discontinues the study treatment before the end of Cycle 1 for any reason other than DLT, or who 
did not receive treatment as planned, will be replaced. Any patient who is not evaluable for DLT 
for any reason shall be replaced at the same dose level as described in Section 6.3. The first 
3 patients treated during the Dose Escalation Part of TED15138 will be replaced. Another 3 
patients will be enrolled in DL1 and the trial will proceed according to the 3+3 design. Patients 
treated in the Expansion 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 1.2 (overall assessments), Section 1.3 
(pharmacokinetic, pharmacodynamics, biomarker, and immunogenicity assessments) and 
described below. The results of the evaluation will be recorded in the eCRF pages until the patient 
is not followed anymore.  
During the Dose Escalation Part of the study, patients must be hospitalized as indicated below: 
 Cycle 1 for DL1 and DL2: for the duration of the SAR440234 infusion (1 to 19 hours) and 
for 72 hours after completion of each infusion, for safety monitoring. 
 Cycle 1 for DL ≥3: for the duration of the SAR440234 infusion (1 to 19 hours) and for 
72 hours after completion of each infusion, for safety monitoring. In Week 1 only, patients 
will receive an infusion of SAR440234 on Day 4. Therefore, patients in DL ≥3 will be 
hospitalized continuously from Day 1 of Week 1 until 72 hours after completion of the 
third infusion, ie, for 11 days. 
 Cycle 2 for all dose levels: for the duration of the SAR440234 infusion (1 to 19 hours) and 
for 72 hours after completion of each subsequent infusion in Week 1 and Week 2 only, for 
safety monitoring. Hospitalization for all the other infusions is on the day of infusion only. 
 Cycle 3 and beyond for all dose levels: on the day of infusion, only. 
During the Expansion Part of the study, patients will be hospitalized as indicated below: 
 Cycle 1 if the RP2D is DL1 or DL2: for the duration of the SAR440234 infusion (1 to 
19 hours) and for 72 hours after completion of each subsequent infusion, for safety 
monitoring. 
 Cycle 1 if the RP2D is DL ≥3: for the duration of the SAR440234 infusion (1 to 19 hours) 
and for 72 hours after completion of each subsequent infusion, for safety monitoring. In 
Week 1 only, patients will receive an infusion of SAR440234 on Day 4. Therefore, 
patients in DL ≥3 will be hospitalized continuously from Day 1 of Week 1 until 72 hours 
after completion of the third infusion, ie, for 11 days. 
 Cycle 2 and beyond for all dose levels: on the day of infusion only. 
If a subsequent treatment cycle is delayed for ≥10 days, treatment should resume with the lead-in 
doses, and the hospitalization guidelines for a first cycle of treatment must be applied.  
Patients who are not hospitalized will return to the site weekly for administration of SAR440234 
and assessments as indicated in the study flow charts. An end of treatment visit will be performed 
30 days after the last administration of the IMP (see flow charts for investigations to be 
performed). The patients will be followed until recovery or consolidation of any SAE or 
IMP-related AE. 
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12.2 
BASELINE EVALUATION  
The pretreatment examinations are to be performed within 14 days 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. 
 Medical history and clinical examination: including medical, surgery, and disease history; 
prior anticancer therapies; physical examination; ECOG performance status, height, 
weight; vital signs (temperature, blood pressure, heart rate, respiration rate, oxygen 
saturation); and record of prior and concomitant medications. 
 Laboratory assessments: 
- 
Coagulation: international normal ratio, prothrombin time, activated partial 
thromboplastin time, fibrinogen, D-dimer, 
- 
Chemistry: 
- 
Liver function tests: AST, ALT, gamma glutamyl transferase (GGT), total 
bilirubin, direct bilirubin, alkaline phosphatase, 
- 
Electrolytes: sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, 
- 
Renal function tests: BUN, creatinine, uric acid, estimated CrCl (Cockroft-Gault 
formula), 
- 
Others: LDH, albumin, and total protein. 
- 
Urinalysis: dipstick for pH, protein, glucose, 
- 
Serum or urine pregnancy test, when appropriate: a negative serum or urine pregnancy 
test result must be obtained within 14 days prior to the first dose of the IMP, 
- 
Serology tests: hepatitis B antigen, hepatitis C antibodies, 
- 
Pro-inflammatory cytokines, CRP, and ferritin, 
- 
Cytogenetic/FISH data collection. 
 Disease assessment: 
- 
Bone marrow aspiration, 
- 
Bone marrow biopsy, 
- 
Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
percentage of blasts, platelet count, 
- 
Immunophenotyping (peripheral blood and bone marrow), 
- 
Extramedullary leukemic localizations: hepatomegaly, splenomegaly, 
lymphadenopathy, dermal involvement, gingival infiltration, and any other 
examinations as clinically indicated to be performed to assess disease status at 
baseline, 
- 
Minimal residual disease Baseline assessment. 
 12-lead ECG. 
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 
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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.  
Adverse events will be collected from the time the informed consent is signed. 
12.3 
BEFORE THE FIRST INVESTIGATIONAL MEDICINAL PRODUCT ADMINISTRATION 
ON THE FIRST DAY OF TREATMENT  
The following assessments are to be performed on Cycle 1 Day 1. 
 Physical examination including height and weight; ECOG performance status; vital signs 
(temperature, blood pressure, heart rate, respiration rate, oxygen saturation). 
 Laboratory assessments: 
- 
Coagulation: international normal ratio, prothrombin time, activated partial 
thromboplastin time, fibrinogen, 
- 
Chemistry: 
- 
Liver function tests: AST, ALT, GGT, total bilirubin, direct bilirubin, alkaline 
phosphatase, 
- 
Electrolytes: sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, 
- 
Renal function tests: BUN, creatinine, uric acid, estimated CrCl (Cockroft-Gault 
formula), 
- 
Others: LDH, albumin, and total protein. 
- 
Pro-inflammatory cytokines, CRP, and ferritin, 
- 
SAR440234 pharmacokinetics and ADA (predose). 
 Disease assessment: 
- 
Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
percentage of blasts, platelet count, 
- 
Extramedullary leukemic localizations: hepatomegaly, splenomegaly, 
lymphadenopathy, dermal involvement, gingival infiltration. 
12.4 
DURING THE TREATMENT PERIOD OF CYCLE 1  
See flow charts in Section 1.2 and Section 1.3. 
 Administration of SAR440234: Days 1, 4 (DL ≥3), 8, 15, 22, 29, and 36.  
 Blood samples for serum CRP/ferritin, and cytokines (including IL-6 and IFN-γ), 
SAR440234, and ADA, will be collected at the time points specified in the 
pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An 
additional blood sample for analysis of CRP/ferritin and cytokines will be taken at onset of 
CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
 AE enquiry and record. 
 Changes in concomitant medications record. 
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 Physical examination including weight; ECOG performance status on IMP administration 
days.  
 Vital signs (temperature, blood pressure, heart rate, respiration rate, oxygen saturation) 
5 minutes before start of infusion, 0.5 hours after start of infusion, at the end of infusion, 
1 hour, 2 hours, and 4 hours post-infusion, then daily. During infusion, temperature, blood 
pressure, heart rate, oxygen saturation, and respiratory rate must be monitored every 
30 minutes. Vital signs (heart rate, respiration rate) must be monitored continuously during 
CRS Grade ≥2, if this occurs. 
 Laboratory assessments: 
- 
Coagulation: international normal ratio, prothrombin time, activated partial 
thromboplastin time on IMP administration days, daily after the first administration, 
for patients in Cycle 1 of the Dose Escalation Part, 
- 
Chemistry: on IMP administration days, and every 8 hours after the start of drug 
administration and for at least 72 hours after the end of infusions for patients in the 
Dose Escalation Part and the Expansion Part: 
- 
Liver function tests: AST, ALT, GGT, total bilirubin, direct bilirubin, alkaline 
phosphatase, 
- 
Electrolytes: sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, 
- 
Renal function tests: BUN, creatinine, uric acid, estimated CrCl (Cockroft-Gault 
formula), 
- 
Others: LDH, albumin, and total protein. 
 Pro-inflammatory cytokines, CRP, and ferritin as indicated in Section 1.3.1 and  
Section 1.3.3. 
 ECG: must be monitored continuously during CRS Grade ≥2, if this occurs. 
 Oxygen saturation (pulse oximetry): must be monitored continuously during 
CRS Grade ≥2, if this occurs. 
 Disease assessment: 
- 
Bone marrow aspiration is required on Day 42 (±2 days). Additional bone marrow 
aspirate shall be performed as clinically indicated, or if any of the following occurs: 
decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile 
neutropenia Grade 3 and Grade 4, anemia Grade 4 occurs with onset in >14 days 
before or after Day 42, 
- 
Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
percentage of blasts, platelet count. Hematology will be evaluated daily during 
Cycle 1, 
- 
Immunophenotyping (peripheral blood and bone marrow) on Day 42 (±2 days), 
- 
Extramedullary leukemic localizations: hepatomegaly, splenomegaly, 
lymphadenopathy, dermal involvement, gingival infiltration or others on Day 1, 
- 
Minimal residual disease, as clinically indicated. 
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The investigations and tests scheduled for Day 42 may be performed on the next day if 
treatment continues after the current cycle; in this case the tests and investigations must be 
performed before start of next infusion: 
- 
Extramedullary leukemic localization 
- 
ECOG PS, Body Weight 
- 
Physical examination  
- 
Blood chemistry 
If the treatment won't be continued after the current cycle, all the planned tests and 
investigations for Day 42 must be performed on the day that the decision is made that the 
patient will not continue treatment with SAR440234. 
12.5 
DURING FURTHER CYCLES  
See flow charts in Section 1.2 and Section 1.3.4. 
 Administration of SAR440234: Days 1, 8, 15, 22, 29, and 36. 
 Blood samples for serum CRP/ferritin, and cytokines (including IL-6 and IFN-γ), 
SAR440234, and ADA, will be collected at the time points specified in the 
pharmacokinetic, pharmacodynamic, biomarker and immunogenicity flowcharts. An 
additional blood sample for analysis of CRP/ferritin and cytokines will be taken at onset of 
CRS Grade ≥2 if it occurs, or as soon as it is diagnosed. 
 AE enquiry and record. 
 Changes in concomitant medications record. 
 Physical examination including weight; ECOG performance status on IMP administration 
days.  
 Vital signs (temperature, blood pressure, heart rate, respiration rate, oxygen saturation) 
5 minutes before start of infusion, 0.5 hours after start of infusion, at the end of infusion, 
1 hour, 2 hours, and 4 hours post-infusion, then as clinically indicated at least until 
72 hours from the start of infusion. During infusion, temperature, blood pressure, heart 
rate, oxygen saturation, and respiratory rate must be monitored every 30 minutes. Vital 
signs must be monitored continuously during CRS Grade ≥2, if this occurs. 
 Laboratory assessments: 
- 
Coagulation: international normal ratio, prothrombin time, activated partial 
thromboplastin time, fibrinogen on IMP administration days. 
- 
Chemistry on IMP administration days and 3 subsequent days during Cycle 2, Week 1 
and Week 2, then weekly thereafter: 
- 
Liver function tests: AST, ALT, GGT, total bilirubin, direct bilirubin, alkaline 
phosphatase, 
- 
Electrolytes: sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, 
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- 
Renal function tests: BUN, creatinine, uric acid, estimated CrCl (Cockroft-Gault 
formula), 
- 
Others: LDH, albumin, and total protein. 
 Pro-inflammatory cytokines, CRP, and ferritin as indicated in Section 1.3.4.  
 Disease assessment: 
- 
Bone marrow aspiration is required on Day 42 (±2 days). Additional bone marrow 
aspirate shall be performed as clinically indicated, or if any of the following occurs: 
decreased neutrophil count Grade 4, decreased platelet count Grade 4, febrile 
neutropenia Grade 3 and Grade 4, anemia Grade 4 occurs with onset in >14 days 
before or after Day 42, 
- 
Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
percentage of blasts, platelet count, daily during Week 1 of Cycle 2, then weekly 
during all subsequent infusions and cycles, 
- 
Immunophenotyping (peripheral blood and bone marrow) on Day 42 of Cycle 2 only 
and in blood on Day 42 of Cycle 3 and subsequently. Further samples for 
immunophenotyping may be taken at the discretion of the Investigator and as clinically 
indicated, 
- 
Extramedullary leukemic localizations: hepatomegaly, splenomegaly, 
lymphadenopathy, dermal involvement, gingival infiltration, on Day 1 of each cycle. 
- 
Minimal residual disease, as clinically indicated. 
All of these tests may be repeated when clinically indicated. 
Blood hematology is not required in D2-D7 of cycle 3 and subsequent. Blood chemistry is not 
required in D2-D4 and in D9-D11 of cycle 3 and subsequent. 
The investigations and tests scheduled for Day 42 may be performed on the next day if 
treatment continues after the current cycle; in this case the tests and investigations must be 
performed before start of next infusion: 
- 
Blood hematology, 
- 
Extramedullary leukemic localization, 
- 
ECOG PS, Body Weight, 
- 
Physical examination, 
- 
Vital signs, 
- 
Coagulation, 
- 
Blood chemistry. 
If the treatment won't be continued after the current cycle, all the planned tests and 
investigations for Day 42 must be performed on the day that the decision is made that the 
patient will not continue treatment with SAR440234. 
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12.6 
END OF TREATMENT VISIT (TO BE PERFORMED WITHIN 30 DAYS AFTER THE 
LAST ADMINISTRATION OF THE INVESTIGATIONAL MEDICINAL PRODUCT)  
See flow charts in Section 1.2.2, Section 1.2.4, and Section 1.3.4. 
 AE enquiry and record. 
 Changes in concomitant medications record. 
 Physical examination including weight; ECOG performance status; vital signs 
(temperature, blood pressure, heart rate, respiration rate, oxygen saturation). 
 Laboratory assessments: 
- 
Coagulation: international normal ratio, prothrombin time, activated partial 
thromboplastin time, 
- 
Chemistry: 
- 
Liver function tests: AST, ALT, GGT, total bilirubin, direct bilirubin, alkaline 
phosphatase, 
- 
Electrolytes: sodium, potassium, calcium, magnesium, phosphorus, bicarbonate, 
- 
Renal function tests: BUN, creatinine, uric acid, estimated CrCl (Cockroft-Gault 
formula), 
- 
Others: LDH, albumin, and total protein. 
- 
Urinalysis: dipstick for pH, protein, glucose, 
- 
Serum or urine pregnancy test. 
 Disease assessment: 
- 
Hematology: hemoglobin, hematocrit, white blood cell count with differential, 
percentage of blasts, platelet count, 
- 
Immunophenotyping (peripheral blood), 
- 
Extramedullary leukemic localizations: hepatomegaly, splenomegaly, 
lymphadenopathy, dermal involvement, gingival infiltration. 
 12-lead ECG. 
Blood sampling for immunogenicity assessments of SAR440234 will be performed at the end of 
treatment visit. If the patient does not plan to return for an EOT visit, the EOT evaluation must be 
performed on the day that the decision is made that the patient will not continue treatment with 
SAR440234. 
12.7 
PERIOD POST END OF TREATMENT  
Follow up will be performed for patients with ongoing SAEs regardless of relationship to IMP 
and ongoing IMP-related AEs 30 days after the last IMP administration, and for patients with new 
IMP-related AEs/SAEs. Those events will be followed until resolution or stabilization as 
described in Section 10.5.3 and Section 11.1.2. Follow-up visits are to be performed monthly until 
initiation of another anti-cancer therapy, disease progression, study cut-off date, or death.  If a 
patient is unable to return to clinic for monthly follow-up visits, the investigator must obtain 
follow up information via telephone call and record review. 
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Patients achieving stable disease (SD), CR, CRi, or PR or non-CR/nonprogressive disease (PD) 
should be followed until disease progression or initiation of another specific antitumor treatment 
to collect either the date of PD or the initiation of further antitumor therapy. 
The Site Investigator will evaluate the patient’s symptoms, physical examination, vital signs, and 
laboratory tests each month. If the Investigator finds evidence to indicate a change in disease 
status, the Investigator will obtain a bone marrow aspirate to confirm the change. If there is no 
perceived change in disease status, additional testing is not required. 
12.8 
POST STUDY CUT-OFF PERIOD  
If a patient continues to benefit from the treatment after the second study cut-off date, the patient 
can continue study treatment until disease progression, unacceptable toxicity or patient request. 
Such patients will be followed until 30 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. 
No follow-up information will be collected after these patients discontinue study treatment, with 
the exception of all SAEs regardless of relationship to study treatments and all IMP-related AEs 
still ongoing at the end of study treatment and any new treatment-related AE/SAEs occurring after 
the end of study treatment which will be followed until resolution/stabilization. 
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13 
STATISTICAL CONSIDERATIONS  
The content of this section is the Statistical Analysis Plan for the study. 
13.1 
DETERMINATION OF SAMPLE SIZE  
It is anticipated that approximately 72 patients (67 to 77 patients) will be enrolled in this study 
(Dose Escalation and Expansion Parts).  
13.1.1 Dose escalation part  
This study aims to establish the MTD as well as the RP2D of SAR440234 according to DLTs 
observed. 
It is anticipated that approximately 30 to 40 DLT-evaluable patients will be entered in the Dose 
Escalation Part. The actual sample size will vary depending on DLTs observed and number of 
dose levels actually explored. 
Any patient who is not evaluable for DLT, ie, who discontinues the study treatment before the end 
of Cycle 1 for any reason other than DLT will be replaced. The first 3 patients treated during the 
Dose Escalation Part of TED15138 will be replaced. Another 3 patients will be enrolled in DL1 
and the trial will proceed according to the 3+3 design. 
13.1.2 Expansion part  
A Simon’s 2-stage design (optimal) will be used. If ≤3 responses (CR, CRi or PR) are observed 
on the first 17 patients treated, the alternative hypothesis of at least 40% response rate will be 
rejected. Otherwise, accrual will continue to the full sample size of 37 patients. Overall, this 
procedure has 90% statistical power (1-sided alpha of 10%) to reject a null response rate of 20% 
in a 1-sample test for a binomial proportion (East version 6.4, Cytel Software, Cambridge, MA). 
Eleven (11) responses on 37 patients will be necessary to reject the null hypothesis. 
13.2 
PATIENT DESCRIPTION  
13.2.1 Disposition of patients  
Disposition of patients will be depicted by intended dose level (including the Expansion Part) for 
both the patient study status and also for the patient analysis populations. For patient study status, 
the total number of patients for each one of the following categories will be presented in the 
clinical study report using a flow-chart diagram or summary table: 
 Registered patients are patients who sign the study informed consent, and who plan to 
receive the study treatment. 
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The all-treated/safety population is defined in Section 13.3.1. 
 Patients who discontinue study treatment and reasons for discontinuation. 
 Patients evaluable for DLT assessment. 
 Pharmacokinetic population. 
 Pharmacodynamic population. 
 Activity/efficacy population. 
For all categories of patients, percentages will be calculated using the number of exposed patients 
(all-treated/safety population). Reasons for treatment discontinuation will be provided in tables 
giving numbers and percentages by dose level. 
Additionally, the analysis populations for safety, efficacy, pharmacokinetics, and 
pharmacodynamics will be summarized in a table by patient counts for the all-treated/safety 
population.  
13.2.2 Protocol deviations  
Major protocol deviations, which compromise the evaluation of the MTD, will be derived 
adequately (mainly algorithmically and/or following medical review) and determination of 
deviations will be finalized based on data review conducted prior to database lock. 
Decisions made on a patient’s status will be documented. 
13.3 
ANALYSIS POPULATIONS  
13.3.1 All-treated/safety population  
The all-treated/safety population is defined as all registered patients who have given their 
informed consent and who have received at least 1 dose (even incomplete) of SAR440234. 
13.3.2 Patients evaluable for DLT assessment  
The DLT-evaluable population in the Dose Escalation Part will include all patients who have 
received at least 5 out of 6 weekly IV administration of SAR440234 in DL1 and DL2, patients 
who have received at least 6 out of 7 IV administrations of SAR440234 in DL ≥3, and patients 
who discontinue the IMP before completion of Cycle 1 because of a DLT.  
A complete safety evaluation should be performed during the DLT observation period, and a DLT 
form should be completed at the end of the cycle. This concerns both patients followed up to the 
end of the evaluation period and patients who experienced a DLT validated by the Study 
Committee. Patients with incomplete safety evaluation during the DLT observation period and 
who experience a DLT during this period will be considered as evaluable for DLT. 
The first 3 patients treated will be excluded from the DLT-evaluable population. 
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13.3.3 Pharmacokinetic population  
The pharmacokinetic population will include patients from the all-treated/safety population with 
at least 1 evaluable drug concentration after IMP administration (whatever the cycle and even if 
dosing is incomplete). 
13.3.4 Activity/efficacy population  
The activity/efficacy population will be defined as all patients with at least 1 post-Baseline 
evaluable disease assessment allowing status evaluation. 
13.3.5 Anti-drug antibody population  
The ADA population will include all patients from the all-treated/safety population with at least 
1 available ADA result after IMP administration. 
13.4 
STATISTICAL METHODS  
Unless otherwise specified, analyses will be descriptive and performed based on the 
all-treated/safety population. 
Continuous data will be summarized using number of available data, mean, standard deviation 
(StD), median, minimum, and maximum for each dose level. Categorical and ordinal data will be 
summarized using number and percentage of patients in each dose level.  
13.4.1 Demographics and baseline characteristics  
Standard demographic and baseline characteristics (including age, race, gender, ECOG 
performance status), medical history, cancer diagnosis will be collected at baseline and described 
by dose level. Genetic and molecular profiles of disease, if available, will be collected before 
study treatment. 
Parameters will be summarized by dose level and overall using descriptive statistics.  
13.4.2 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed and summarized by dose level within the 
all-treated/safety population.  
Duration of IMP exposure is defined as: last dose date – first dose date + 28 days, regardless of 
unplanned intermittent discontinuations. 
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In addition, in the Expansion Part of the study, dose information will be assessed for the following 
variables: 
 The number of infusions. 
 The cumulative dose at Cycle k is the sum of all doses from Cycle 1 to and including 
Cycle k, where k is based on Investigator’s report. 
 Actual dose intensity (ADI), defined as the cumulative dose divided by the number of 
weeks on study treatment. 
 Relative dose intensity (RDI), defined as the ratio of the actual dose intensity to the 
planned dose intensity. The relative dose intensity is an indicator of the feasibility of the 
chosen schedule of administration. 
 Cycle delay: A cycle is deemed to have been delayed if start date of the current cycle – 
start date of previous cycle >42 days.  
 Dose delay: A dose is deemed to have been delayed if the infusion is made >1 day later 
than the scheduled administration. 
 Dose omission: A dose is considered to be omitted if the dose is not administered at the 
scheduled visit and 1 or more doses are given afterwards. 
 Dose interruption: An infusion is considered to be interrupted if the administration is 
stopped before the infusion is completed, regardless of whether or not the infusion is 
restarted. 
 Dose reduction and reason for dose reduction. 
Dose information variables will be summarized descriptively (n, mean, standard deviation, 
median, Q1:Q3, minimum, and maximum). Analyses will be performed based on the number of 
patients and on the number of cycles. 
13.4.3 Prior/concomitant medication/therapy  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the ATC class (anatomic category) and the first 3 digits of the 
ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
summarized. Patients will be counted once in each ATC category (anatomic or therapeutic) linked 
to the medication.  
Medications of specific interest such as antibiotics and hematopoietic growth factors (G-CSF, 
GM-CSF and erythropoietin or 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. 
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13.4.4 Analyses of safety data  
13.4.4.1 Dose-limiting toxicities  
The DLTs observed during DLT observation period will be summarized by dose level, as well as 
AEs that meet the DLT criteria in subsequent cycles. Details will be provided (characteristics of 
DLTs) by patient. 
13.4.4.2 Analyses of adverse events  
Adverse events will be collected from the time informed consent is signed until at least 30 days 
after the last administration of the IMP, and will be categorized according to NCI-CTCAE v4.03, 
except for CRS, which will be graded according to the 2014 NCI Consensus Guidelines 
(Table 10). All AEs will be classified by system organ class and preferred term according to the 
latest available version of the MedDRA dictionary. 
Definitions 
Period of observation: The observation period will be divided into 3 segments: pretreatment, 
on-treatment, and post-treatment. The pretreatment period is defined as the time from when the 
patients give informed consent up to the first administration of the 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. 
Pretreatment AEs are defined as any AE occurring during the pretreatment period. 
Treatment-emergent AEs are defined as AEs that developed or worsened (according to the 
Investigator 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 will be provided in the summary. For patients with multiple occurrences of the same 
PT, the maximum grade will be used.  
The primary focus of AE reporting will be the 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 all-treated/safety population within each dose level. 
Sorting within tables should ensure the same presentation for the set of all AE within the 
observation period (pre-, on-, and post-treatment). For that purpose, the table of all TEAEs 
presented by system organ class and preferred term will be sorted by internationally agreed order, 
unless otherwise specified. Full 4-level hierarchy will be provided, if needed. 
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The following TEAE summaries will be generated: 
 Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE, 
- 
Any Grade ≥3 TEAE, 
- 
Any Grade 3 or 4 TEAE, 
- 
Grade 5 TEAE (any TEAE with a fatal outcome during the treatment period), 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation. 
Analysis of CRS 
The following summaries will be provided: 
 Number (%) of patients experiencing CRS (all grades and by grade). 
 Number (%) of patients experiencing CRS by action taken with study treatment. 
 Number (%) of patients with infusion of occurrence. 
 Duration of CRS event (in hours). 
13.4.4.3 Deaths  
The following deaths summaries will be generated; 
 Number (%) of patients who died by study period (pre-treatment, on-treatment, post-
treatment). 
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 will be used. Hematological and clinical 
biochemistry toxicities will be assessed from laboratory test parameters. Each test result will be 
graded by NCI-CTC (v4.03). The number of patients with abnormal laboratory tests at baseline 
will be presented by grade. The frequency of patients in each grade of lab tests during treatment 
will be summarized. When appropriate, the summary table will present the frequency of patients 
with any grade of abnormal laboratory tests and with Grade 3 to 4 of abnormal laboratory tests. 
For patients with Grade 3 to 4 abnormal laboratory tests, additional analyses will be conducted to 
describe time to onset and dose to onset. 
Further analyses could be provided to explore the dose and time to onset of safety endpoints of 
interest. 
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13.4.4.5 Vital signs  
The summary statistics (including mean, median, standard error, 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 
dose level. Mean changes from baseline with the corresponding standard error (or boxplots) will 
be plotted over time (at same time points) in each dose level. 
13.4.4.6 Immunogenicity  
13.4.4.6.1 Immunogenicity status  
The observation period for ADAs will be divided into 2 periods:  
 The ADA pretreatment period will be defined as the time that informed consent is signed 
until the first study treatment administration. 
 The ADA on-study observation period will be defined as the time from the first study 
treatment administration until the end of the study. 
Patients with at least 1 evaluable ADA result during the ADA pretreatment period will be 
considered as evaluable at baseline. Patients with at least 1 evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period. 
Definitions:  
 Pre-existing ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
 Treatment-induced ADA, defined as ADA that developed at any time during the 
ADA on-study observation period in patients without pre-existing ADA (including 
patients without pretreatment samples). 
 Treatment boosted ADA, defined as pre-existing ADA with a significant increase in the 
ADA titer during the study compared to the baseline titer.  
 ADA positive patients, defined as patients with at least 1 treatment-induced or 
treatment-boosted ADA positive sample at any time following the first study treatment 
administration. 
 ADA prevalence, defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
 ADA incidence, defined as the number of ADA positive patients divided by the number of 
evaluable patients. 
The immunogenicity of SAR440234 will be assessed by summarizing the number (%) of patients 
with pre-existing ADA and ADA negative at baseline, and by summarizing the number (%) of 
ADA positive patients (including treatment-induced ADA and treatment boosted ADA) during the 
on-study observation period.  
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ADA prevalence and ADA incidence will be also described.  
A summary table will summarized the number of evaluable patients, number of positive, negative 
and inconclusive patients. The prevalence and the incidence will be also reported. 
For all patients, an individual listing of immunogenicity sample results (positive, negative or 
inconclusive) will be provided together with the associated titer. 
13.4.4.6.2 Immune response:  
The following definitions will be used to describe the immune response: 
 Transient ADA response: ADA detected only at 1 time point during treatment or ADA 
detected at ≥2 time points during treatment including EOT with less than a 16-week period 
between the first and last ADA-positive samples (irrespective of any negative samples in 
between) and the last sample should be ADA negative. 
 Persistent ADA response: ADA detected at ≥2 time points during treatment including EOT 
with ≥16-week period between the first and the last ADA-positive samples (irrespective of 
any negative samples in between) and if the last 2 samples are positive, irrespective of the 
time period in between. 
 Indeterminate ADA response: only the last sampling time point is positive. 
13.4.4.6.3 Immunogenicity impact on pharmacokinetics  
The impact of positive immune response will be evaluated on efficacy, pharmacokinetic, and 
safety endpoints when relevant. 
13.4.5 Analyses of pharmacokinetic variables  
Individual concentrations and pharmacokinetic parameters of SAR440234 will be summarized by 
descriptive statistics (such as mean, geometric mean, median, SD, standard error of the mean, 
coefficient of variation, minimum, and maximum). Individual and mean profiles will be presented 
graphically. Dose proportionality and accumulation will also be assessed on relevant parameters 
in the pharmacokinetic population. 
13.4.6 Analysis of cytokines  
Individual concentrations of each measured cytokine will be tabulated and summarized by 
descriptive statistics (such as mean, geometric mean, median, SD, standard error of the mean, 
coefficient of variation, minimum, and maximum). Potential correlation with other parameters 
such as safety and pharmacokinetic endpoints will be also investigated. 
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13.4.7 Analysis of immunophenotyping data  
CD123 receptor density at baseline and after treatment will be summarized with descriptive 
statistics. Subpopulation analyses including effector/target ratio will be tabulated with standard 
descriptive statistics. 
13.4.8 Analyses of antitumor activity/efficacy variables  
The ORR and other efficacy will be summarized using descriptive statistics by hematological 
malignancies. A 95% 2-sided confidence interval will be computed for ORR using the 
Clopper-Pearson method. 
13.5 
INTERIM ANALYSIS  
In the Expansion Part, an interim analysis is planned when 17 patients are treated in order to 
decide, based on preset criteria, if the recruitment of planned additional patients is justified. If 3 or 
fewer responses (CR, CRi, or PR) are observed on the first 17 patients, the study will be stopped 
for futility.  
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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 consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki, and the International Council for 
Harmonisation (ICH) guidelines for good clinical practice (GCP), all applicable laws, rules, and 
regulations. 
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 ethics committee (IRB/IEC). All participants should be informed to the fullest extent 
possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, with the name of the patient filled in and personally dated by the patient or by the patient’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written informed consent form will be provided to the 
patient. 
For patients age 16 to 18 years, the informed consent form should be signed, name filled in and 
personally dated by the patient’s parent(s) or by the patient’s legally acceptable representative, 
and by the person who conducted the informed consent discussion. Local law must be observed in 
deciding whether 1 or both parents/guardians consent is required. If only 1 parent or guardian 
signs the consent form, the Investigator must document the reason for only 1 parent or guardian’s 
signature. 
In addition, participants age 16 to 18 years will assent as detailed below or will follow the ethics 
committee (IRB/IEC) approved standard practice for pediatric participants at each participating 
center (age of assent to be determined by the IRB’s/IEC’s or be consistent with the local 
requirements): 
 Participants who can read the assent form will do so before writing their name and dating 
or signing and dating the form. 
 Participants who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
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 Participants who can understand but who can neither write nor read will have the assent 
form read to them in presence of an impartial witness, who will sign and date the assent 
form to confirm that assent was given. 
In relation to the population of patients exposed in the trial (ie, pediatric/minor patients), the 
IRB/IEC should ensure proper advice from specialist with pediatric expertise (competent in the 
area of clinical, ethical, and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
The informed consent form and the assent form used by the Investigator for obtaining the 
patient’s informed consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate ethics committee (IRB/IEC) for approval/favorable opinion. 
14.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate ethics 
committee (IRB/IEC), and is required to forward to the respective other party a copy of the 
written and dated approval/favorable opinion signed by the Chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda, Investigator’s CV, etc) and the date of the review should be clearly stated on the written 
ethics committee (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the ethics committee (IRB/IEC) should be informed as soon as possible. 
They should also be informed of any event likely to affect the safety of patients or the continued 
conduct of the clinical trial, in particular any change in safety. All updates to the Investigator’s 
Brochure will be sent to the ethics committee (IRB/IEC) and to health authorities (competent 
regulatory authority), as required by local regulation. 
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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 eCRF, 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 eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical 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 eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allowing the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRF (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 eCRFs (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 eCRFs 
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 eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor when available in the eCRF 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 
eCRF. 
15.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document, 
which is maintained in the Sponsor trial master file. 
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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 Subinvestigator 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 eCRFs, 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/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical 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 cause the delegated Investigator staff/Subinvestigator 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. 
Patient race or ethnicity (American Indian or Alaska Native; Asian; Black or African American; 
Native Hawaiian or Other Pacific Islander; White) will be collected in this study because these 
data are required by several regulatory authorities (eg, on afro American population for FDA, on 
Japanese population for the PMDA in Japan, or on Chinese population for the CFDA in China). 
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 IECs/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 are 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/IEC 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. 
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 in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or 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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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/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical 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/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
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acute leukemia. Leukemia. 2004 ;18(2):219-26. 
10. Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, et al. Elevated expression of 
IL-3R alpha in acute myelogenous leukemia is associated with enhanced blast proliferation, 
increased cellularity, and poor prognosis. Blood. 2002;100(8):2980-88. 
11. De Waele M, Renmans W, Vander Gucht K, Jochmans K, Schots R, Otten J, et al. Growth 
factor receptor profile of CD34+ cells in AML and B-lineage ALL and in their normal bone 
marrow counterparts. Eur J Haematol. 2001;66(3):178-87. 
12. Ehninger A, Krmaer M, Röllig C, Thiede C, Borhhauser M, von Bonin M, et al. Distribution 
and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood 
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13. Florian S, Sonneck K, Hauswirth AW, Krauth MT, Schernthaner GH, Sperr WR, et al. 
Detection of molecular targets on the surface of CD34/CD38- stem cells in various myeloid 
malignancies. Leuk Lymphoma. 2006;47(2):207-22. 
14. Muñoz L, Nomdedéu JF, López O, Carnicer MJ, Bellido M, Aventín A, et al. Interleukin-3 
receptor alpha chain (CD123) is widely expressed in hematologic malignancies. 
Haematologica. 2001;86(12):1261-69. 
15. Saber H, Del Valle P, Ricks TK, Leighton JK. An FDA oncology analysis of CD3 bispecific 
constructs and first-in-human dose selection. Regul Toxicol Pharmacol. 2017;90:144-52. 
16. Duff GW. Expert Scientific Group on Phase One Clinical Trials: Final Report; 30th November 
2006. Stationery Office 2006; 25-27. 
17. Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human 
pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? 
MAbs. 2011;3(1):61-6. 
18. Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine 
release syndrome after blinatumomab treatment related to abnormal macrophage activation 
and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-57. 
19. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for diagnosis, standardization of 
response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute 
myeloid leukemia. J Clin Oncol. 2003;21(24):4642-49. 
20. Mitchell CD, Richards SM, Kinsey SE, Lilleyman J, Vora A, Eden TO; Medical Research 
Council Childhood Leukaemia Working Party. Benefit of dexamethasone compared with 
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21. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. 
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J 
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22. Chatenoud L, Ferran C, Legendre C, Thouard I, Merite S, Reuter A, et al. In vivo cell 
activation following OKT3 administration. Systemic cytokine release and modulation by 
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23. Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in 
patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment 
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24. Reagan JL, Fast LD, Safran H, Nevola M, Winer ES, Castillo JJ, et al. Cellular 
immunotherapy for refractory hematological malignancies. J Transl Med. 2013;11:150. 
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25. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a 
serious adverse event following the administration of T-cells transduced with a chimeric 
antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843-51. 
26. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity 
management of 19-28z CAR T-cell therapy in B cell acute lymphoblastic leukemia. Sci Transl 
Med. 2014;6(224):224ra25. 
27. Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M. Treatment of chronic lymphocytic 
leukemia with genetically targeted autologous T-cells: case report of an unforeseen adverse 
event in a phase I clinical trial. Mol Ther. 2010;18(4):666-68. 
28. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen 
receptor-modified T-cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509-18. 
29. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-95. 
30. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 
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31. Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for acute 
lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):567-72. 
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meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum. 
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33. Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, et al. Therapeutic efficacy 
of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-
onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52(3):818-25. 
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international working group to standardize response criteria for myelodysplastic syndromes. 
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International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes. Blood. 
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38. NCI-CTC Version 3.0 reference, accessible through the NCI website at 
http://ctep.info.nih.gov/reporting/ctc.html. 
 
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19 
APPENDICES  
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information  
DEFINITIONS 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
3. Postmenopausal female: 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient, 
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the nonhormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
CONTRACEPTION GUIDANCE 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following (during the protocol-defined time frame in Section 6.8): 
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent, 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
 Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration 
(during the protocol-defined time frame). 
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 Refrain from donating sperm for the duration of the study and for 3 months after study 
completion or the last dose of study treatment. 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described below: 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb: 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
 oral 
 injectable 
Highly Effective Methods That Are User Independenta 
 Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb: 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case TWO highly effective methods of contraception should be utilized during the treatment period and for at least 38 days 
after the last dose of study treatment. 
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COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant  
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure. 
Female participants who become pregnant  
 The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 
Any pregnancy complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post study pregnancy-related SAE considered reasonably related to the study treatment by 
the Investigator will be reported to the Sponsor as described in Section 10.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. 
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Appendix B 
List of CYP substrates with a narrow therapeutic range  
Patients treated or intended to be treated with drugs presented as CYP substrates with narrow 
therapeutic range should be monitored carefully for safety. Examples of such drugs are as follows: 
 
In vivo CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A Narrow Therapeutic Range 
Substrates 
CYP enzyme 
NTR Substratesa 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP2D6 
Thioridazine 
CYP3A 
Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, quinidine, sirolimus, 
tacrolimus, cisapride, astemizole, terfenadine, pimozide 
a CYP substrates with a narrow therapeutic range – drugs with an exposure-response relationship that indicates that relatively small increases 
in their exposure levels by co-administered CYP inhibitors may lead to safety concerns 
Abbreviations: CYP=cytochrome P450, NTR=narrow therapeutic range. 
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Appendix C 
ECOG Performance Status Scale  
 
Performance 
Status 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair (37). 
 
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Appendix D 
Response Criteria for ALL  
The following response criteria are extracted from the NCCN Guidelines, Version 2.2016, for 
ALL. 
Response Criteria for Blood and Bone Marrow 
 Complete response (CR): 
- 
No circulating blasts or extramedullary disease, 
- 
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central 
nervous system involvement. 
- 
Trilineage hematopoiesis and <5% blasts, 
- 
ANC >1000/μL, 
- 
Platelets >100 000/μL, 
- 
No recurrence for 4 weeks. 
 Complete response with incomplete blood count recovery (CRi): 
- 
Meet all criteria for CR except platelet count and/or ANC. 
 Overall response rate (ORR = CR + CRi). 
 Refractory disease: 
- 
Failure to achieve CR at the end of induction. 
 Progressive disease (PD): 
- 
Increase of at least 25% in the absolute number of circulating or bone marrow blasts or 
development of extramedullary disease. 
Relapsed disease: 
- 
Reappearance of blasts in blood or bone marrow (>5%) or in any extramedullary site 
after a CR. 
Response Criteria for Mediastinal Disease 
CT of chest with IV contrast and PET imaging should be performed to assess. 
 Complete remission (CR): complete resolution of mediastinal enlargement by computed 
tomography. For patients with a previous positive PET scan, a post-treatment residual 
mass of any size is considered a CR as long as it is PET negative. 
 Partial remission (PR): >50% decrease in the sum of the product of the greatest 
perpendicular diameters (SPD) of the mediastinal enlargement. For patients with a 
previous positive PET scan, a post-treatment PET must be positive in at least one 
previously involved site. 
 Progressive disease (PD): >25% increase in the SPD of the mediastinal enlargement. For 
patients with a previous positive PET scan, a post-treatment PET must be positive in at 
least one previously involved site.  
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 No response (NR): failure to qualify for PR or PD. 
 Relapse: recurrence of mediastinal enlargement after achieving CR. For patients with a 
previous positive PET scan, a post-treatment PET must be positive in at least one 
previously involved site. 
Further details are provided online at the following NCCN website: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site  
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Appendix E 
Revised International Prognostic Scoring System in MDS  
 
 
 
 
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Appendix F 
Response criteria for AML  
 
 
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Appendix G 
Response criteria for HR-MDS  
Based on the revised criteria for HR MDS (34). 
 
Measurement of response/treatment effect in MDS 
 
ALTERING DISEASE NATURAL HISTORY 
 
1. Complete remission (CR)  
 
Bone marrow evaluation: Repeat bone marrow showing less than 5% myeloblasts with normal 
maturation of all cell lines, with no evidence for dysplasia.* When erythroid precursors constitute 
less than 50% of bone marrow nucleated cells, the percentage of blasts is based on all nucleated 
cells; when there are 50% or more erythroid cells, the percentage blasts should be based on the 
nonerythroid cells. 
 
Peripheral blood evaluation (absolute values must last at least 2 months)†: 
Hemoglobin greater than 11 g/dL (untransfused, patient not on erythropoietin) 
Neutrophils 1500/mm3 or more (not on a myeloid growth factor) 
Platelets 100 000/mm3 or more (not on a thrombopoetic agent) 
Blasts, 0% 
No dysplasia* 
 
2. Partial remission (PR) (absolute values must last at least 2 months): 
All the CR criteria (if abnormal before treatment), except: 
Bone marrow evaluation: Blasts decreased by 50% or more over pretreatment, or a less advanced 
MDS FAB classification than pretreatment. Cellularity and morphology are not relevant. 
 
3. Stable disease 
Failure to achieve at least a PR, but with no evidence of progression for at least 2 months. 
 
4. Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, increase 
in the percentage bone marrow blasts, or progression to an MDS FAB subtype more advanced 
than pretreatment. 
 
5. Relapse after CR or PR—one or more of the following: 
a) Return to pretreatment bone marrow blast percentage. 
b) Decrement of 50% or greater from maximum remission/response levels in granulocytes or 
platelets. 
c) Reduction in hemoglobin concentration by at least 2 g/dL or transfusion dependence.§ 
 
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6. Disease progression 
a) For patients with less than 5% blasts: a 50% or more increase in blasts to more than 5% blasts. 
b) For patients with 5% to 10% blasts: a 50% or more increase to more than 10% blasts. 
c) For patients with 10% to 20% blasts: a 50% or more increase to more than 20% blasts. 
d) For patients with 20% to 30% blasts: a 50% or more increase to more than 30% blasts. 
e) One or more of the following: 50% or greater decrement from maximum remission/response 
levels in granulocytes or platelets, reduction in hemoglobin concentration by at least 2 g/dL, or 
transfusion dependence.§ 
 
7. Disease transformation 
Transformation to AML (30% or more blasts). 
 
CYTOGENETIC RESPONSE 
(Requires 20 analyzable metaphases using conventional cytogenetic techniques.) 
Major: No detectable cytogenetic abnormality, if preexisting abnormality was present. 
Minor: 50% or more reduction in abnormal metaphases. 
Fluorescent in situ hybridization may be used as a supplement to follow a specifically defined 
cytogenetic abnormality. 
 
HEMATOLOGIC IMPROVEMENT (HI) 
(Improvements must last at least 2 months in the absence of ongoing cytotoxic therapy.)† 
Hematologic improvement should be described by the number of individual, positively affected 
cell lines (eg, HI-E; HI-E 1 HI-N; HI-E 1 HI-P 1 HI-N). 
 
1. Erythroid response (HI-E) 
Major response: For patients with pretreatment hemoglobin less than 11 g/dL, greater than 2 g/dL 
increase in hemoglobin; for RBC transfusion-dependent patients, transfusion independence. 
Minor response: For patients with pretreatment hemoglobin less than 11 g/dL, 1 to 2 g/dL increase 
in hemoglobin; for RBC transfusion-dependent patients, 50% decrease in transfusion 
requirements. 
 
2. Platelet response (HI-P) 
Major response: For patients with a pretreatment platelet count less than 100 000/mm3, an 
absolute increase of 30 000/mm3 or more; for platelet transfusion-dependent patients, stabilization 
of platelet counts and platelet transfusion independence. 
Minor response: For patients with a pretreatment platelet count less than 100 000/mm3, a 50% or 
more increase in platelet count with a net increase greater than 10 000/mm3 but less than 
30 000/mm3. 
 
3. Neutrophil response (HI-N) 
Major response: For absolute neutrophil count (ANC) less than 1500/mm3 before therapy, at least 
a 100% increase, or an absolute increase of more than 500/mm3, whichever is greater. 
Minor response: For ANC less than 1500/mm3 before therapy, ANC increase of at least 100%, but 
absolute increase less than 500/mm3. 
 
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4. Progression/relapse after HI: One or more of the following: a 50% or greater decrement from 
maximum response levels in granulocytes or platelets, a reduction in hemoglobin concentration by 
at least 2 g/dL, or transfusion dependence.§ 
For a designated response (CR, PR, HI), all relevant response criteria must be noted on at least 
2 successive determinations at least 1 week apart after an appropriate period following therapy 
(eg, 1 month or longer). 
 
*The presence of mild megaloblastoid changes may be permitted if they are thought to be 
consistent with treatment effect. However, persistence of pretreatment abnormalities (eg, 
pseudo-Pelger-Huet cells, ringed sideroblasts, dysplastic megakaryocytes) are not consistent with 
CR. 
†In some circumstances, protocol therapy may require the initiation of further treatment 
(eg, consolidation, maintenance) before the 2-month period. Such patients can be included in the 
response category into which they fit at the time the therapy is started. 
§In the absence of another explanation such as acute infection, gastrointestinal bleeding, 
hemolysis, and so on. 
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Appendix H 
Grading System and mitigation strategy for CRS, based on 2014 
NCI Consensus guidelines  
Grade 
Toxicity 
Intervention 
Grade 1 
 
Fever, nausea, fatigue, headache, 
myalgias, malaise, without 
life-threatening complications. 
 
Vigilant supportive care. 
 
Assess and treat infection if present. 
 
Fluid resuscitation. 
 
Provide antipyretics and analgesics, if 
needed.  
Grade 2 
 
Oxygen requirement <40% FIO2.  
 
Hypotension responsive to low-dose or 
single vasopressor. 
 
Grade 2 organ toxicity 
 
As for Grade 1, but monitor cardiac and 
other organ function closely. 
 
Consider corticosteroids and/or anti-IL6 
therapy for patients with advanced age 
or multiple co-morbidities. 
Grade 3 
 
Oxygen requirement >40% FIO2. 
 
Hypotension responsive to high-dose or 
multiple vasopressors. 
 
Grade 3 organ toxicity. 
 
Grade 4 increase in ALT or AST. 
 
As for Grade 2, but with the addition of 
corticosteroids and/or anti-IL6 therapy. 
Grade 4 
 
Life-threatening symptoms. 
 
Requirement for mechanical ventilation. 
 
Grade 4 organ toxicity, excluding 
increase in ALT or AST. 
 
As for Grade 2, but with the addition of 
corticosteroids and/or anti-IL6 therapy. 
Grade 5 
Death 
 
Grading system based on the 2014 NCI Consensus Guidelines (29, 31). 
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Appendix I 
National Cancer Institute common terminology criteria for adverse 
events  
Refer to NCI-CTCAE v4.03 (38) 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 J 
Guidelines for the management of tumor lysis syndrome (TLS).  
TLS is a metabolic derangement that is the result of rapid destruction of tumor cells. TLS is 
common in hematological malignancies and can cause several side effects; some of them may 
become life-threatening. Early recognition of TLS and initiation of therapy is essential.  
Intravenous hydration is recommended for all patients prior to start of SAR440234 infusions and 
is left to Investigator judgment for further cycles.  
The patients at greatest risk of TLS are those with a high tumor burden prior to treatment.  
These patients should be monitored closely and appropriate precautions should be taken (such as 
use of prophylactic uric acid lowering agents (eg, allopurinol or rasburicase) and regular 
measurement of electrolytes.  
This appendix provides parameters to be checked in case of TLS suspicion and recommendations 
for TLS management. Abnormalities listed in this appendix do not exclusively support TLS 
diagnosis and any differential diagnosis also needs to be assessed, if appropriate.  
TLS may present with laboratory parameters changes, clinical manifestations, or both as indicated 
in Appendix Table 1.  
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Appendix Table 1 - Tumor lysis syndrome definitions 
 
 
During the 1st cycle of SAR440234 treatment, every 8 hours after the start of infusion for the next 
72 hours, the monitoring of blood chemistry is mandatory (details are provided in protocol).  
Cardiac monitoring and admission to the ICU is required if TLS is established, as well as 
continuing laboratory monitoring every 4-6 hours. Additional measures to treat metabolic 
derangements associated with TLS may be required, as shown in Appendix Table 2. 
 
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Prophylaxis against TLS may be required depending on the patient’s risk for TLS, as described 
below.  
Low-risk is defined as: 
- 
Patients with low tumor burden (WBC ≤ 50 x 109/l and normal LDH level) 
- 
Patients receiving low intensity cytoreductive therapy 
- 
Normal pre-existing uric acid 
- 
Adequate hydration 
- 
No tumor infiltration in the kidney 
High-risk is defined as: 
- 
Hematological malignancies with high proliferative rate 
- 
High tumor burden (WBC ≥ 50 x 109/l and high LDH level) 
- 
Elevated uric acid level 
- 
Patients receiving intensive cytoreductive therapy 
- 
Poor hydration 
- 
Leukemia infiltration of the kidney 
Recommendations for intravenous hydration during SAR440234 treatment in patients at high 
risk for TLS, include the following: 
- 
Normal saline solution 3 L/m2/d, unless no symptoms of acute renal dysfunction and 
oliguria.  
- 
Maintain urine output ≥ 100 ml/m2/h.  
- 
Diuretics may be required to maintain urine output at ≥ 100 ml/m2/h: mannitol 0.5 mg/kg 
or furosemide 0.5 – 1.0 mg/kg. 
For high risk patients, prophylactic treatment with allopurinol should begin 2 to 3 days before the 
start of antineoplastic therapy and continue for 10 to 14 days, as described in Appendix Table 3. 
Rasburicase is indicated for patients with the following features: 
- 
High-risk of TLS development 
- 
Urgent need to initiate therapy in a patient with a high bulk of malignant disease 
- 
In a situation where adequate hydration may be difficult or impossible 
- 
Acute renal failure 
The dose for rasburicase is indicated in Appendix Table 3. Redosing must be individualized.  
Recommendations regarding the selection of allopurinol and/or rasburicase are summarized in 
Appendix Table 4. 
 
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Appendix Table 2 - Specific recommendations for treatment of TLS  
 
 
Hyperphosphatemia: ≥ 2.1 mmol/L 
Removing phosphates from i.v. solutions 
Oral phosphate binders: e.g. aluminum hydroxide 
orally at 50-150 mg/kg/24 h q6h 
Peritoneal dialysis, hemodialysis or continuous 
venovenous hemofiltration may be required in a 
case of severe hyperphosphatemia. 
Calcium infusion is prohibited! 
Hypocalcemia: ≤ 1.75 mmol/L (serum) or ionized 
calcium is ≤ of ionized local limit 
Treatment not required if asymptomatic. 
Symptomatic hypocalcemia (muscle cramps and 
spasms, paresthesias, arrhythmias, heart block, 
hypotension, confusion, delirium, hallucination, 
seizures) requires treatment: 
Calcium gluconate 50 – 100 mg/kg/dose i.v. 
Hyperkalemia 
Moderate and asymptomatic (≥ 6.0 mmol/L): 
Avoid i.v. and oral potassium 
ECG and cardiac rhythm monitoring 
Sodium polystyrene sulphonate 1 g/kg with 
50 % sorbitol po or per rectum 
Severe (>7.0 mmol/L) and/or symptomatic 
Same as above, plus 
Calcium gluconate (100–200 mg/kg) i.v. 
and/or 
Regular insulin (0.1 unit/kg i.v.) + D25 
(2 mL/kg) i.v. 
Dialysis 
Renal dysfunction (uremia)  
 
Fluid and electrolyte management 
Uric acid and phosphate management 
Adjust renally excreted drug doses 
Dialysis (hemo- or peritoneal) 
Hemofiltration (CAVH, CVVH, CAVHD or CVVHD) 
 
Hyperuricemia:  
uric acid ≥ 476 mcmol/L 
See Appendix Tables 3 and 4 regarding selection 
and dose of hypouricemic agents: 
Allopurinol 
Rasburicase (recombinant urate oxidase). 
 
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Appendix Table 3 - Recommendations on the use of hypouricemic agents 
Allopurinol 
100 mg/m2/dose q8 h (10 mg/kg/d divided q8 h) p.o. 
(maximum 800 mg/d) or 200–400 mg/m2/d in 1–3 divided doses i.v. (maximum 600 mg/d) 
Reduce dose by 50% or more in renal failure  
Reduce 6-mercaptopurine and/or azathioprine doses by 65–75% with concomitant allopurinol 
Adjust doses of drugs metabolized by P450 hepatic microsomal enzymes with concomitant 
allopurinol 
Rasburicase 
Avoid in glucose-6-phosphate dehydrogenase deficient patients. 
Immediate and permanent stop of treatment if methemoglobinemia is result.  
0.05–0.20 mg/kg i.v. over 30 min 
To measure uric acid levels place blood sample immediately on ice to avoid continual 
pharmacological ex vivo enzymatic degradation. 
10% incidence of antibody formation. 
 
Appendix Table 4 - Recommendations on selection of hypouricemic agents 
 
Allopurinol 
Rasburicase 
Uric acid level 
Normal 
Elevated 
Tumor type 
Non-hematological 
Hodgkin’s lymphoma, 
CML 
Burkitt’s lymphoma, 
lymphoblastic 
lymphoma, ALL, AML 
Tumor burden 
WBC count 
≤50 · 109/L 
>50 · 109/L 
LDH 
≤ 2· normal 
>2 · normal 
Cytoreductive 
intensity 
Mild 
Aggressive 
Kidney tumor 
infiltration 
Absent 
Present 
 
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Appendix K Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Clinical Trial Summary. 
Amended protocol [02] (15 February 2019) 
Reasons for amendment 
 Modify allowed chemotherapy to permit use of hydroxyurea, if needed, to control the 
white blood count during Cycle 1 
In section: E03, E08, Clinical Trial Summary “Dose Escalation Part”, Section 7.3 and Section 8.6 
Rationale: Hydroxyurea may help to control the white blood count during the 6 weeks of the DLT 
observation period of the dose escalation and/or during lead-in dosing during Cycle 1 when 
SAR440234 dosing is likely to be subtherapeutic. 
 Clarify wording in the dose delay/reduction section to avoid misinterpretations 
In section: Section 6.5.4, and Section 6.5.5 
Rationale: Dose delay and/or dose reduction are not required if the AE is related to underlying 
leukemia or baseline cytopenia and continuing SAR440234 treatment is considered safe. 
 Clarify wording of DLT definitions 
In section: Clinical Trial Summary “Dose Escalation Part” and Section 6.2.1 
Rationale: AEs caused by the patient’s underlying hematologic malignancy should not be 
considered investigational medical product (IMP)-related and thus should not be deemed DLTs. 
 Require performance of Day 42 assessment on the day that the patient discontinues 
therapy with SAR440234 
In section: Flow charts and Section 1.2.1-1.3.4, Section 6.8.1, Section 12.4, Section 12.5, 
Section 12.6, and Section 12.7 
Rationale: Given the severity of illness and short life expectancy that many patients with relapsed 
or refractory hematologic malignancies exhibit, a patient may not survive long enough or be well 
enough to return to clinic for a Day 42 or EOT visit after discontinuing SAR440234. 
 Require performance of end of treatment (EOT) assessment within 30 days of last 
SAR440234 administration 
In section: Flow charts and Section 1.2.1-1.3.4, Section 6.8.1, Section 12.4, Section 12.5, 
Section 12.6, and Section 12.7 
Rationale: Given the severity of illness and short life expectancy that many patients with relapsed 
or refractory hematologic malignancies exhibit, a patient may not survive long enough or be well 
enough to return to clinic for a Day 42 or EOT visit after discontinuing SAR440234. 
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 Require follow up via telephone call and record review if a patient is unable to return 
to clinic for monthly study visits after discontinuing SAR440234 
In section: Flow charts and Section 1.2.1-1.3.4, Section 6.8.1, Section 12.4, Section 12.5, and 
Section 12.6, and Section 12.7  
Rationale: Given the severity of illness and short life expectancy that many patients with relapsed 
or refractory hematologic malignancies exhibit, a patient may not survive long enough or be well 
enough to return to clinic for a Day 42 or EOT visit after discontinuing SAR440234. 
 Clarify enrollment schedule 
In section: Clinical trial summary, and Section 6.2.1 
Rationale: Since each Cycle 1 Day 1 (C1D1) of each DL starts with a dose that was tested in the 
previous DL and the acute effects are expected to occur within 1 week of administration, 
subsequent patients within a DL may initiate treatment at least 1 week after the first patient in the 
same DL started treatment with SAR440234. 
Amended protocol 01 based on Amendment 01 
Reasons for amendment 
 Clarify some discontinuation criteria 
In section: Clinical trial summary, Section 6.5.4 of the protocol 
Rationale: Description of treatment discontinuation for patients with Grade 3 febrile neutropenia 
or Grade 4 bone marrow hypocellularity has been removed because it was not consistent with the 
more detailed description in Section 6.5.4 
 Modify some Inclusion/Exclusion criteria 
In sections: Clinical trial summary, Section 7.2 and Section 7.3 of the protocol 
Rationale: 
- 
In I 02., the criteria for patients who have relapsed or refractory disease resistant to 
available therapies have been revised. 
- 
In I 03., it has been clarified that patients with B-cell acute lymphoblastic leukemia 
without extramedullary lesions in second or subsequent relapse must have completed 
at least 1 cycle of a salvage regimen before being recruited for any dose level ≥3 
during the dose escalation part. 
- 
I 04. was revised to better define the criteria for inclusion of patients with high risk 
myelodysplasia (HR-MDS). 
- 
I 01. and I 03 are revised to specify that patients must have exhausted available 
treatment options and must not be eligible for any treatment known to provide clinical 
benefit. 
- 
E 03. is revised to exclude patients with a white blood cell count greater than 
30,000/mm3. 
- 
E 05. is added to exclude patients with history of active or chronic autoimmune 
condition that has required or requires therapy. 
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 Define overdose of oral intake 
In section: Section 10.5.5 of the protocol 
Rationale: A criterion for overdose with orally taken Investigational Medicinal Product 
(IMP)/Non-Investigational Medicinal Product (NIMP) has been added as montelukast (NIMP) 
may be taken orally. 
In addition, other minor changes are listed in the description of changes (next section). 
 Update premedication prior to infusion. Additional premedication is now required: 
dexamethasone 20 mg IV and monteleukast 10 mg oral (PO) 4 hours prior to the 
start of SAR440234 
In section: Clinical trial summary, Section 1.2, Section 4.5.3, Section 6.7.1, and Section 8.2 of the 
protocol 
Rationale: Provide maximal protection from acute reactions.  
 Update dose modification rules for Grade 3 and 4 CRS 
In section: Section 6.5.3 (Tables 5 and 6) of the protocol. 
Rationale: To protect patients against the potentially life-threatening consequences of severe 
cytokine release syndrome (CRS). All patients who develop Grade 4 CRS at any time point in the 
study should immediately and permanently discontinue study drug. In addition, only patients who 
experience limited Grade 3 CRS (as defined by 1st occurrence of Grade 3 CRS with recovery to 
baseline or ≤ Grade 1 within 72 hours) should be permitted to resume treatment with appropriate 
dose reductions. 
 Add specific guidelines for the risk stratification, diagnosis, prevention, and 
treatment of tumor lysis syndrome. 
In section: Section 6.7.2 and Appendix J of the protocol 
Rationale: To prevent potentially life-threatening consequences of tumor lysis syndrome, which 
could occur if SAR440234 is highly effective in a patient with a high burden of malignant disease. 
 Add magnesium to blood chemistry. 
In section: Sections 1.2, Section 6.7.2, and Section 12 of the protocol  
Rationale: To prevent potentially life-threatening consequences of tumor lysis syndrome, which 
could occur if SAR440234 is highly effective in a patient with a high burden of malignant disease. 
 
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persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
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According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
An open-label, first-in-human, dose escalation study 
of SAR440234 administered as single agent by 
intravenous infusion in patients with relapsed or 
refractory acute myeloid leukemia (R/R AML), B-cell 
acute lymphoblastic leukemia (B-ALL), or high risk 
myelodysplasia (HR-MDS) 
Protocol number: 
TED15138 
Compound number 
(INN/Trademark): 
SAR440234 
(Not applicable) 
Study phase: 
Phase 1/2A 
Short title: 
Not applicable 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
11-May-2021
Regulatory agency identifier number(s): 
Registry: 
Not applicable 
Enter Registry Name: 
Not applicable 
Total number of pages: 25 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 6 
2 
SAMPLE SIZE DETERMINATION .................................................................................................. 8 
3 
ANALYSIS POPULATIONS ............................................................................................................ 9 
4 
STATISTICAL ANALYSES ........................................................................................................... 10 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 10 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 10 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 11 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 11 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 11 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 11 
4.7 
SAFETY ANALYSES ..................................................................................................................... 11 
4.7.1 
Extent of exposure ......................................................................................................................... 12 
4.7.1.1 
Overall exposure ............................................................................................................................ 12 
4.7.1.2 
SAR444245 exposure .................................................................................................................... 12 
4.7.2 
Adverse events .............................................................................................................................. 13 
4.7.3 
Additional safety assessments ....................................................................................................... 16 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 16 
4.8 
OTHER ANALYSES....................................................................................................................... 18 
4.8.1 
PK analyses ................................................................................................................................... 18 
4.8.2 
Immunogenicity analysis ................................................................................................................ 19 
4.8.3 
Biomarker analyses........................................................................................................................ 20 
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4.9 
INTERIM ANALYSES .................................................................................................................... 20 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 21 
5.1 
APPENDIX 1: LIST OF ABBREVIATIONS .................................................................................... 21 
5.2 
APPENDIX 2: CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................ 22 
5.3 
APPENDIX 3: DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 22 
5.4 
APPENDIX 4: DATA HANDLING CONVENTIONS ....................................................................... 24 
6 
REFERENCES ............................................................................................................................... 25 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 6 
Table 3 - Populations for analyses .................................................................................................................. 9 
Table 4 - Sorting of AE tables ....................................................................................................................... 14 
Table 5 - Analyses of adverse events ........................................................................................................... 15 
Table 6 - Selections for AESIs and other AEs of interest .............................................................................. 16 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study TED15138 is the first version and is based on the 
amended protocol 03 dated 11 July 2019. 
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1 
Current version 
Not Applicable  
Original version 
 
 
 
 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is an open-label, nonrandomized, dose escalation and dose expansion, safety, efficacy, 
pharmacokinetic (PK) and pharmacodynamic (PD) evaluation study of SAR440234 administered 
as a single agent IV infusion every week to patients ≥ 16 years of age with relapsed or refractory 
acute myeloid leukemia (R/R AML), high risk myelodysplastic syndrome (HR-MDS), or B-cell 
lymphoblastic leukemia (B-ALL). 
After a screening period of up to 14 days, participants will receive treatment in one of the two The 
study duration for a patient will include a period for screening of up to 14 days starting from the 
time the patient signs the informed consent form. The cycle duration is 42 days with weekly IMP 
administration (except for Cycle 1 Week 1 in dose level (DL) ≥3 when 2 administrations will be 
given). Patients will continue study treatment as long as a clinical benefit is possible, or until 
disease progression, unacceptable adverse reaction, patient’s decision to stop treatment, or any 
other reason, whichever comes first. 
The study will be performed in two parts:  
• 
Dose Escalation Part with SAR440234 as monotherapy 
• 
Expansion Part with SAR440234 as monotherapy 
Enrollment of patients in the Expansion Part will start after completion of Dose Escalation Part 
and indication of the MTD/RP2D. 
Approximately 72 patients (67 to 77 patients) will be enrolled overall from up to 13 sites. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
 
 
 
• 
Dose Escalation Part: To 
determine the maximum tolerated 
dose (MTD)/maximum 
administered dose (MAD) of 
SAR440234 administered as a 
single agent in patients with R/R 
AML, HR-MDS, or B-ALL, and 
determine the recommended phase 
2 dose (RP2D) for the subsequent 
Expansion Part. 
• 
Expansion Part: To assess the 
activity of single agent SAR440234 
• 
Dose Escalation Part: Incidence of DLT observed 
during the first 42 days following the first 
administration of IMP in the first cycle of treatment. 
• 
Dose Escalation Part: Incidence of allergic 
reactions/hypersensitivity and CRS/acute infusion 
reactions. 
• 
Expansion Part: Preliminary anti-leukemia activity 
as defined by the IWG for MDS or AML: Overall 
response rate (ORR) including CR, CRi, and 
partial response, Duration of response, Event-free 
survival. 
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Objectives 
Endpoints 
at the RP2D in patients with R/R 
AML, or HR-MDS. 
Secondary 
 
 
 
• 
To characterize the safety profile of 
SAR440234 including cumulative 
adverse drug reactions. 
• 
To characterize the 
pharmacokinetic profile of 
SAR440234 when administered as 
a single agent. 
• 
To evaluate the potential 
immunogenicity of SAR440234. 
• 
To assess any preliminary 
evidence of hematologic response 
in the Dose Escalation Part. 
• 
The safety profile of SAR440234 in terms of 
treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), and changes in 
laboratory parameters, vital signs, 
electrocardiograms (ECGs), and assessment of 
physical examination. 
• 
Pharmacokinetic parameters of SAR440234: 
Concentration observed at the end of IV infusion, 
maximum concentration observed (Cmax), time to 
reach Cmax, last concentration observed above 
the lower limit of quantification, time of the last 
concentration observed above the lower limit of 
quantification (ie, Clast), concentration observed 
just before treatment administration during 
repeated dosing, area under the plasma 
concentration versus time curve (area under the 
curve (AUC)) calculated using the trapezoidal 
method from time zero to Clast, AUC calculated 
using the trapezoidal method from time zero to 
infinity, AUC calculated using the trapezoidal 
method over the dosing interval (7 days). 
• 
Incidence rate of anti-drug antibody (ADA, ie, anti-
SAR440234 antibody) development. 
• 
In the Dose Escalation Part, preliminary anti-
leukemia activity as defined by IWG for MDS or 
AML, or NCCN for B-ALL. 
Exploratory 
 
 
 
• 
To perform pharmacodynamic 
assessments on blood and bone 
marrow including: 
• 
To measure CD123 
expression in malignant cells 
and kinetics of this expression 
under treatment. 
• 
To monitor CD123 expression 
on normal cells. 
• 
To assess minimal residual 
disease (MRD) in patients 
achieving a complete 
response (CR) or complete 
response with incomplete 
hematological recovery (CRi), 
and correlate MRD with 
clinical outcome. 
• 
To assess T-cell 
subpopulations (eg, CD4, 
CD8) and activation status. 
• 
Assessment of CD123 expression in cells in the 
peripheral blood and bone marrow aspirate. 
Percentage of CD123-expressing cells may be a 
pharmacodynamic biomarker for response to the 
IMP. 
• 
Monitoring of T-cell subpopulations (eg, CD4, 
CD8) and activation status in the peripheral blood 
and bone marrow aspirate. 
• 
Minimal residual disease by molecular biology 
assessment and/or flow cytometry will be 
assessed in bone marrow from patients achieving 
a CR or CRi and correlated with clinical outcome. 
• 
Assessment of plasma cytokine levels in blood at 
specific time points following treatment 
administration to evaluate potential associations of 
cytokine levels with safety and clinical outcomes. 
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Objectives 
Endpoints 
• 
To investigate the relationship 
between CD123 expression, 
disease molecular subtype (as 
defined by marker expression, 
cytogenetics, and/or 
genomics) and parameters of 
clinical response. 
• 
To assess levels of cytokines 
following treatment administration, 
and their relationship with safety 
profile and clinical outcome. To 
explore other indicators of 
antitumor activity. 
2 
SAMPLE SIZE DETERMINATION  
It is anticipated that approximately 72 patients (67 to 77 patients) will be enrolled in this study 
(Dose Escalation and Expansion Parts).  
Dose Escalation Part 
It is anticipated that approximately 30 to 40 DLT-evaluable patients will be entered in the Dose 
Escalation Part. The actual sample size will vary depending on DLTs observed and number of 
dose levels actually explored. 
Any patient who is not evaluable for DLT, ie, who discontinues the study treatment before the end 
of Cycle 1 for any reason other than DLT, or who did not receive treatment as planned, will be 
replaced. 
Expansion Part 
It is hypothesized that SAR440234 would induce a response rate of 40% and that the null 
hypothesis for ORR is 20%. Under these hypotheses and using a Simon 2-stage design (optimal), 
with a 1-sided 10% significance level and a power of 90%, it is planned to enroll 37 patients in the 
Expansion Part of the study. Eleven (11) responses out of 37 patients will be necessary to reject 
the null hypothesis (H0 response rate = 20%). 
An interim analysis of the ORR will be done after treatment of the first 17 patients through 2 
cycles. If 3 or fewer responses (CR, CRi, or PR) are observed, the Expansion Part will be stopped 
due to futility. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses 
Population 
Description 
Screened 
All participants who have given their informed consent.  
All-treated 
All participants from the screened population and exposed to the investigational 
drug, regardless of the amount of treatment administered. 
Efficacy 
All participants from the all-treated population with at least one post-baseline 
evaluable disease assessment allowing status evaluation. 
DLT-evaluable 
All participants in the dose escalation part, who have received at least 5 out of 6, 
weekly IV administrations of SAR440234 in DL1 and DL2, or at least 6 out of 7 IV 
administrations of SAR440234 in DL≥3. Patients who discontinue the IMP before 
completion of Cycle 1 because of a DLT will also be included in the DLT-evaluable 
population. Patient who discontinues the study treatment before the end of Cycle 1 
for another reason than DLT will be replaced. 
Pharmacokinetic (PK) 
All participants from the all-treated population with at least one drug concentration 
post-baseline (whatever the cycle and even if dosing is incomplete). 
ADA 
All participants from the all-treated population with at least 1 available ADA result 
(positive, negative or inconclusive) post-baseline. 
Biomarker 
All participants from exposed population with at least one valid assessment for: 
• 
CRP or ferritin, or  
• 
Cytokines, or 
• 
Disease molecular subtype, or 
• 
immunophenotyping by flow cytometry, or 
• 
MRD. 
For any participant enrolled and treated more than once, only the data associated with the 
first enrollment will be used in any analysis population. The safety experience associated with any 
later enrollment will be reported separately.  
 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation, median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first administration of 
SAR440234. For participants enrolled but not treated, the baseline value is defined as the last 
available value before enrollment. 
Unless otherwise specified, analyses will be performed by part, by dose level (if applicable) and 
overall (if applicable). 
All efficacy analyses will be performed on the efficacy population. Objective response rate, as 
well as all other efficacy variables will be derived using the Investigator’s assessment. 
All safety analyses will be performed on the all-treated population. 
Analysis period  
The analysis period will be divided into 3 segments:  
• The pre-treatment period is defined as the period from when the participants give 
informed consent up to first administration of IMP.  
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration + 30 days. 
• The post-treatment period is defined as the period from the end of the on-treatment 
period, ie, 31 days after the last administration of IMP. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
 
Permanent intervention discontinuation is defined as the discontinuation of SAR440234.  
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The number (%) of participants in the following categories will be provided:  
• Exposed participants  
• Participants who did not complete the study period and main reason for study 
discontinuation. 
In addition, the number (%) of participants screened, screened-failed, enrolled, with 
permanent intervention discontinuation will be provided by country and site.  
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the enrolled 
population. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
No primary efficacy endpoint will be analyzed due to early termination of the clinical trial. 
Primary safety endpoints analyses are defined in Section 4.7. 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
No secondary efficacy endpoint will be analyzed due to early termination of the clinical trial. 
Other secondary endpoints analyses are defined in Section 4.7 (safety), Section 4.8.1  (PK) and 
Section 4.8.2 (immunogenicity).  
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
Tertiary endpoints analyses are defined in Section 4.8.3 (biomarkers).  
4.6 
MULTIPLICITY ISSUES  
No formal testing will be performed. Therefore, no multiplicity issues need to be addressed. 
4.7 
SAFETY ANALYSES  
The analysis of the safety variables will be essentially descriptive, and no testing is planned.  
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4.7.1 Extent of exposure  
4.7.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least one 
dose of any study interventions is administered. 
• Duration of IMP exposure (in weeks) is defined as (Last day of exposure – first day of 
exposure +1)/7. 
- 
The first day of exposure is defined as the first administration date with non-zero dose 
for at least one of the IMP (SAR440234). 
- 
The last day of exposure is the day before the theoretical date of the next 
administration (after the last administration), defined as the last administration date + 7 
days for SAR440234. 
Overall study treatment exposure will be presented in a listing along with the overall number of 
cycles started.  
4.7.1.2 SAR444245 exposure  
The dose information will be assessed by the following: 
• 
Cumulative dose for SAR440234 (ng/kg): the cumulative dose is the sum of all doses from 
cycle 1 day 1 up to treatment discontinuation 
• 
Actual dose intensity (ng/kg/week) for SAR440234: 
ADI = Cumulative dose (ng/kg) / Overall duration of exposure in weeks 
• 
Planned dose intensity (ng/kg/week) for SAR440234: 
PDI = Total planned dose (ng/kg) / Overall duration of exposure in weeks 
The total planned dose for SAR440234 will be calculated by the sum of the theoretical 
planned dose (ie, the intended dose as per CRF) over the duration of treatment. 
• 
The relative dose intensity (RDI, in %) for SAR440234 is defined as  
Relative Dose Intensity = (
) x 100 
It is an indicator of the feasibility of the chosen schedule of administration. 
A listing will be provided for cumulative dose, actual dose intensity and relative dose intensity. 
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Dose or cycle modifications 
• 
Cycle delay: A cycle is deemed to have been delayed if start date of the current cycle – 
start date of previous cycle >42 days.  
• 
Dose delay: A dose is deemed to have been delayed if the infusion is made >1 day later 
than the scheduled administration.  
• 
Dose omission: A dose is considered to be omitted if the dose is not administered at the 
scheduled visit and 1 or more doses are given afterwards. 
• 
Dose interruption: An infusion is considered to be interrupted if the administration is 
stopped before the infusion is completed, regardless of whether or not the infusion is 
restarted.  
• 
Dose reduction:  a dose is deemed to have been reduced if the dose taken by a patient is 
lower than 80% of the intended dose. 
• 
Reason for dose reduction. 
Dose information variables will be provided in a listing: 
• 
Cycle/day of occurrence 
• 
Dose reduction Y/N 
• 
Dose omission Y/N 
• 
Dose interruption Y/N 
• 
Cycle delay Y/N 
4.7.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) 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 Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs reported during the pre-treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.   
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The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the grade is missing for 1 of the treatment-emergent occurrences of an AE, the 
grade will be imputed with the maximal severity of the other occurrences. If the grade is missing 
for all the occurrences, the grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. Summaries 
will be provided for all grades combined and for grade ≥3 (including grade 5). Missing grades, if 
any, will be included in the “all grades” category.  
The AE tables will be sorted as indicated in Table 4.  
Table 4 - Sorting of AE tables 
AE presentation 
Sorting rules 
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa,b 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the AE incidence.  
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
 
Analysis of all adverse events 
The overview of TEAEs with the details below will be generated: 
• Any TEAE  
• Any grade ≥3 TEAE 
• Any treatment emergent SAE 
• Treatment related TEAEs (overall and for each individual drug) 
• Treatment related TEAEs of Grade ≥ 3 (overall and for each individual drug) 
• Serious treatment related TEAEs (overall and for each individual drug) 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period)  
• Any TEAE leading to permanent partial intervention discontinuation (for each individual 
drug) 
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• Any TEAE leading to permanent full intervention discontinuation 
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3.  
Table 5 - Analyses of adverse events 
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLT and PT 
Primary SOC and PT 
TEAE related to IMP (overall and for each drug) as per 
Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC and PT  
Treatment emergent SAE related to IMP (overall and for each 
drug) as per Investigator’s judgment 
Primary SOC and PT 
TEAE leading to permanent full intervention discontinuation 
Primary SOC and PT 
TEAE leading to permanent partial intervention discontinuation (for 
each individual drug) 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
Pre-treatment AE 
Primary SOC and PT 
Post-treatment AE 
Primary SOC and PT 
TEAE leading to dose interruption 
Primary SOC and PT 
TEAE leading to dose modification (including dose reduction, dose 
omission and cycle delay, excluding dose interruption) 
Primary SOC and PT 
 
Analysis of deaths 
Deaths will be analyzed through a listing with following information: 
- 
Death date 
- 
Study period 
- 
Reason of death 
- 
For AE with fatal outcome: PT, date of onset, relationship 
Analysis of adverse events of special interest (AESIs) and other AEs of interest  
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 6. Listings with PT and grade will be provided. 
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Table 6 - Selections for AESIs and other AEs of interest 
AESIs and other AEs of interest 
Selection 
DLT during cycle 1 
e-CRF specific DLT page 
Pregnancy of a female participant as well as 
pregnancy occurring in a female partner of a 
male participant 
e-CRF specific pregnancy page 
Symptomatic overdose with IMP/NIMP 
e-CRF specific tick box in overdose page 
CRS 
e-CRF specific category in AE page 
 
Further analyses of Cytokine release syndrome (CRS) with a listing providing a more detailed 
description of CRS by patient:  
- 
Action taken 
- 
Relationship to IMP according to Investigator’s opinion 
- 
Number of episodes 
- 
Onset of first occurrence CRS (at the first infusion and subsequent infusions) 
- 
Day of onset from infusion (by category 1 day/ 2 to 3 days/ More than 3 days when 
applicable) 
- 
Duration (in days) (by category 1 day/ 2 to 3 days/ More than 3 days) 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology  
- 
Hemoglobin and coagulation: hemoglobin, prothrombin time (PT), activated partial 
thromboplastin time, fibrogen, D-dimer and international normalized ratio (INR) 
- 
Platelet count 
- 
White blood cells: white blood cells (WBC) count, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils, leukocytes 
- 
Hematocrit 
- 
Blasts 
• Biochemistry 
- 
Electrolytes: sodium, potassium, calcium, phosphate, bicarbonate/carbon dioxide, 
albumin, protein, magnesium  
- 
Renal function: serum creatinine, estimated creatinine clearance by Cockcroft-Gault 
formula, blood urea nitrogen (BUN), uric acid 
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- 
Liver parameters: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, lactate dehydrogenase (LDH), gamma glutamyl 
transpeptidase (GGT), total and direct bilirubin 
• Urinalysis  
- 
Qualitative urinalysis: protein, glucose, pH 
• Pregnancy: urine, serum 
• Serology: hepatitis B virus surface antigen, hepatitis C virus antibody 
• Pro-inflammatory cytokines, CRP, and ferritin 
• Cytogenetic/FISH data collection  
• Vital signs: heart rate, systolic and diastolic blood pressure, respiratory rate, oxygen 
saturation, weight, body surface area (BSA), temperature and ECOG PS (0, 1, 2, 3, 4). 
• ECG 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification (ULOQ) will be replaced by ULOQ value. 
For hematological parameters and some selected biochemistry parameters, Sanofi generic ranges 
(LLN, ULN) are defined and will be used for grading. For other biochemistry parameters, grading 
will be derived using local laboratory normal ranges.  
Analyses according to potentially clinically significant abnormality (PCSA) and NCI 
CTCAE grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version specified in the protocol. 
Analyses according to NCI CTCAE grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
In addition, for basophils, eosinophils, monocytes, creatinine clearance, eGFR, hematocrit, uric 
acid, PH, uric acid, blood urea nitrogen, potentially clinically significant abnormality (PCSA) 
analyses will be performed based on the PCSA list currently in effect at Sanofi at the time of the 
database lock. 
For laboratory variables above, vital signs and ECG variables, the incidence of participants with at 
least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For laboratory variables graded by NCI-CTCAE, 
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• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.   
• The number (%) of participants with abnormal laboratory tests during the treatment-
emergent period will be summarized by grade.  When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided. 
4.8 
OTHER ANALYSES  
4.8.1  PK analyses   
Pharmacokinetic parameters of SAR440234 will be analyzed under the responsibility of Sanofi, 
Pharmacokinetics, Dynamics and Metabolism (PKDM) department. Pharmacokinetic parameters 
will be determined by non-compartmental analysis using PKDMS V3.1 (running Phoenix 
software). 
The PK parameters will include, but may not be limited to the following: 
 
Parameters 
Definition/calculation 
Ceoi 
Concentration observed at the end of intravenous infusion 
Cmax 
Maximum concentration observed 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of 
quantification 
tlast 
Time of the last concentration observed above the lower limit of 
quantification (ie, Clast) 
Ctrough 
Concentration observed just before treatment administration 
during repeated dosing 
AUClast 
Area under the plasma concentration versus time curve 
calculated using the trapezoidal method from time zero to time 
of the last concentration observed above the lower limit of 
quantification (ie, Clast) 
AUC 
Area under the concentration versus time curve calculated 
using the trapezoidal method from time zero to time infinity 
according to: 
 AUC = AUClast + Clast/λz 
where λz is the slope of the regression line of the observed 
terminal phase of the concentration versus time curve, in semi-
logarithmic scale 
AUC0-T 
Area under the concentration versus time curve calculated 
using the trapezoidal method during a dosing interval (T) 
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Descriptive statistics (arithmetic mean, standard deviation, geometric mean, coefficient of 
variation (%), median, minimum and maximum) for concentrations and PK parameters of 
SAR440234 as well as associated plots will be provided by Sanofi, PKDM. 
All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics. 
4.8.2 Immunogenicity analysis  
The immunogenicity of SAR440234 will be presented for all patients through an individual listing 
of immunogenicity sample results (positive, negative or inconclusive) together with the associated 
titer, Ctrough value, the immunogenicity status of the patient and associated characterization of the 
immune response (transient, persistent, indeterminate) for positive ones. 
The impact of positive immune response will be evaluated on pharmacokinetic, and safety 
endpoints when relevant. 
Participant’s ADA status 
• Participants with pre-existing ADAs correspond to participants with ADAs present in 
samples drawn before first administration of intervention. Participants with missing ADA 
sample at baseline will be considered as without pre-existing ADA. 
• Participants with treatment-emergent ADA correspond to participants with at least one 
treatment-induced/boosted ADA sample. 
- 
Participants with treatment-induced ADAs correspond to participants with ADAs 
that developed during the treatment-emergent (TE) period and without pre-existing 
ADA (including participants without pre-treatment samples). 
- 
Participants with treatment-boosted ADAs correspond to participants with pre-
existing ADAs that are boosted during the TE period to a significant higher titer than 
the baseline. A 2-fold serial dilution schema is used during titration, so at least a 4-fold 
increase will be considered as significant. 
• Participants without treatment-emergent ADA correspond to participants without 
treatment-induced/boosted ADA and without any inconclusive sample during the TE 
period. 
• Participants with inconclusive ADA are defined as participants which cannot irrefutably 
be classified as with or without treatment-emergent ADA. 
Kinetics of ADA response 
Kinetics of ADA response will be derived for participants with treatment-induced/boosted ADA 
considering ADA samples collected during the TE period and post-treatment period. 
• Time to onset of ADA response is defined as the time period between the first IMP 
administration and the first treatment-induced/boosted ADA.  
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• Duration of ADA response is defined as the time between the first treatment-induced/ 
boosted ADA and the last treatment-induced/boosted ADA, irrespective of negative 
samples or positive samples not reaching the boosted threshold in-between. ADA duration 
will be summarized only for participants with persistent ADA response.  
- 
A positive sample (boosted positive sample for participants with pre-existing ADA) 
occurring after the TE period will be considered as treatment-induced/boosted ADA if 
a previous treatment-induced/boosted ADA occurred during the TE period and less 
than 16 weeks before this sample. 
• Persistent ADA response is defined by treatment-induced/boosted ADA with a duration 
of ADA response of at least 16 weeks.  
• Transient ADA response is defined by treatment-induced/boosted ADA with a duration 
of ADA response of less than 16 weeks and the last sample is not treatment-
induced/boosted.  
• Indeterminate ADA response is defined by treatment-induced/boosted ADA that are 
neither persistent nor transient. 
ADA response variable: 
• ADA incidence is defined as the proportion of participants found to have seroconverted 
(treatment-induced ADAs) or boosted their pre-existing ADA response (treatment-boosted 
ADAs) at any time point during the TE period. 
4.8.3 Biomarker analyses  
 
Plasma levels of pro-inflammatory cytokines, including interleukin-6 and interferon-γ, as well as 
blood levels of 2 acute phase proteins, C-reactive protein (CRP) and ferritin, will be assessed 
during the trial. 
Several immune populations and sub-populations will be assessed through immunophenotyping 
performed on blood and bone marrow samples. Different panels will be investigated such as the 
blasts, the plasmacytoid dendritic cells and basophils, the T cells, and the NK cells, granzyme B 
and interferon-γ, as well as analysis of T cell functional status including frequency of Tregs 
(CD4+CD25+CD127-) and expression of activation markers such as PD-1 and CD25. 
All biomarkers will be summarized by dose level at baseline and over time by using descriptive 
statistics. For cytokines, the number of values below the LLOQ will be provided and for the 
computation of summary statistics, LLOQ/2 will be used to impute the test results with below 
LLOQ (BLOQ, ie, value<LLOQ).  
4.9 
INTERIM ANALYSES  
Not applicable due to early termination of the clinical trial. 
 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1: LIST OF ABBREVIATIONS  
 
ADA: 
 anti-drug antibody  
ADI: 
 actual dose intensity 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
 alanine aminotransferase  
AST: 
 aspartate aminotransferase  
AUC: 
 area under the curve 
B-ALL: 
B-cell acute lymphoblastic leukemia 
BUN: 
blood urea nitrogen  
CR: 
 confirmed response 
CRF: 
 case report form 
CRi: 
 complete response with incomplete hematologic recovery  
CRS: 
cytokine release syndrome  
DL: 
dose level 
DLT: 
dose limiting toxicity  
ECG: 
 electrocardiogram 
eCRF: 
Electronic case report form 
FISH: 
 fluorescence in situ hybridization,  Eastern Cooperative Oncology Group 
GGT: 
 gamma glutamyl transpeptidase 
HLT: 
high level term 
HR-MDS: 
high risk myelodysplastic syndrome 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IV: 
intravenous 
IWG: 
International Working Group  
LDH: 
 lactate dehydrogenase  
LLT: 
lower-level term 
MAD: 
maximum administered dose  
MDS: 
 myelodysplastic syndrome  
MedDRA: 
medical dictionary for regulatory activities 
MRD: 
minimal residual disease 
MTD: 
maximum tolerated dose 
NCCN: 
National Comprehensive Cancer Network  
NIMP: 
 non-investigational medicinal product 
ORR: 
 overall response rate 
PD: 
pharmacodynamic  
PDI: 
 planned dose intensity 
PK: 
pharmacokinetic  
PR: 
 partial response 
PT: 
preferred term 
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R/R AML: 
relapsed or refractory acute myeloid leukemia 
RDI: 
relative 
RP2D: 
recommended phase 2 dose 
SAE: 
 serious adverse event 
SAP: 
statistical analysis plan 
SOC: 
system organ class 
TE: 
 treatment-emergent 
TEAE: 
 treatment-emergent adverse event 
WBC: 
 white blood cells  
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2: CHANGES TO PROTOCOL-PLANNED ANALYSES  
Not applicable. 
5.3 
APPENDIX 3: DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the exposed 
population. 
Demographic and baseline characteristics  
• age in years as quantitative variable and in categories (([16-18],[19-24],[25-40],[41-
60],[61-75], ≥78) 
• gender (Male, Female) 
• race: 
- 
White 
- 
Black 
- 
Asian 
- 
Native Hawaiian or Other Pacific Islander 
- 
American Indian or Alaska Native 
- 
Not reported 
- 
Unknown 
• ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
• weight (kg) 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) at baseline 
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Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Medical (or surgical) history includes relevant history of previous pathologies and smoking status. 
Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated primary 
SOC using the MedDRA version currently in effect at Sanofi at the time of database lock.  
Specific disease characteristics at diagnosis includes: 
• 
Time from initial diagnosis of disease (AML, Leukemia/Myelodysplasia or B-ALL) to 
first study treatment administration (in years), 
• 
Diagnosis type, 
• 
Among patients with AML diagnosis: 
- 
Staging 
- 
Risk Group 
- 
FLT3-ITD mutation (Yes, No, Unknown) 
- 
NPM1 mutation (Yes, No, Unknown) 
- 
IDH2 mutation (Yes, No, Unknown) 
• 
Among patients with B-ALL diagnosis: 
- 
Staging 
- 
Risk Group 
Concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Concomitant medications are any interventions received by the participant 14 days prior to 
registration of the study, or at any time during the study in addition to the IMP.  
The concomitant medications will be summarized for the all-treated population, by anatomic and 
therapeutic level. The summaries will be sorted by decreasing frequency of anatomic category 
(ATC). In case of equal frequency, alphabetical order will be used. Participants will be counted 
once in each ATC category (anatomic or therapeutic) linked to the medication.  
Anticancer therapies  
• 
Prior anti-cancer therapies   
Prior anti-cancer treatments are collected by regimen in the eCRF. The following 
variables will be collected/derived and presented in a listing: 
- 
Intent of prior anti-cancer therapy as collected in eCRF 
- 
If conditioning therapy, transplant (Yes, No) 
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- If yes, type of transplant (allogeneic or autologous) 
- 
Number of prior lines of treatment in advanced setting. 
- 
Reason for discontinuation of the last regimen 
- 
Best response to the last regimen 
- 
Time from last progression date to first study drug administration (months) 
- 
Time from start of last prior anti-cancer therapy (last regimen start date) up to last 
progression (months) 
- 
Duration of last prior anti-cancer therapy (last regimen end date - last regimen start 
date) (months) 
• 
Prior surgery: listing providing information on any prior surgery related to cancer, type of 
procedure (Preferred Term) and time from the last surgery to the first study treatment 
administration (months) 
• 
Prior radiotherapy: listing providing information on any prior radiotherapy related to 
cancer, intent, intent of last prior radiotherapy, time from the last radiotherapy to the first 
study treatment administration (months) overall and by intent (curative and palliative) and 
location of prior radiation therapy by intent 
5.4 
APPENDIX 4: DATA HANDLING CONVENTIONS  
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, ECG and ADA will be used for 
computation of baseline, the worst on-treatment value, analysis according to PCSAs/NCI grade, 
and the shift summaries for safety. 
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6 
REFERENCES  
Not applicable 
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