Clinical trial NCT04954326
Conditions: Acute Lymphoblastic Leukemia
Keywords: Oncology / Haematology Phase II Acute Lymphoblastic Leukemia Parallel group Pegaspargase Pharmacokinetics comparability Lyophilized pegaspargase Liquid pegaspargase Pegaspargase formulation Randomized, open-label
Sponsor: Institut de Recherches Internationales Servier
Start date: 2021-05-07; Completion date: 2022-05-20
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations during the induction phase after a single IV dose in newly diagnosed paediatric patients with ALL

Detailed description:

Arms: arm 1: Lyophilized S95014 reconstituted will provide 5 mL of extractable volume with the concentration of 750 U/mL. The vial of lyophilized powder (3.750 U/vial) is reconstituted with 5.2 mL of Sterile Water for Injection to obtain a 750 U/mL solution for single use. arm 2: Liquid S95014 is provided as 3.750 U per 5 mL solution in a single use vial to obtain a 750 U/mL solution for single use.
Interventions: intervention 1: Lyophilized S95014 intervention 2: Liquid S95014
Intervention descriptions: intervention 1: Lyophilized S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase.

Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol. intervention 2: Liquid S95014 will be intravenously administered over 1 hour at the dose of 2500 U/m2 at Day 3 of the induction phase.

Patients will receive other backbone chemotherapy agents as per ALL-MB 2015 protocol.

Protocol documents:
Prot_000.pdf: 
I.R.I.S.
Institut de Recherches Internationales Servier
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
A multicentre, Phase II Randomized study, Open-label, with 2-
arm Parallel Group, comparing the pharmacokinetics of the 
Liquid and the Lyophilized Formulations of pegaspargase 
(S95014) in Treatment of Paediatric Patients with Newly-
Diagnosed Acute Lymphoblastic Leukemia (ALL) 
Study brief title 
Pharmacokinetics 
comparability 
study 
of 
Liquid 
and 
Lyophilized pegaspargase (S95014) formulations in ALL 
Study public title 
A study comparing the blood levels of both pegaspargase 
(S95014) formulations (liquid vs lyophilized) in the Treatment 
of Paediatric Patients with Acute Lymphoblastic Leukemia 
(ALL) 
Test drug code 
S95014 / pegaspargase / Oncaspar® 
Indication 
Acute Lymphoblastic Leukemia 
Development phase 
II 
Protocol code  
CL2-95014-002 
EudraCT Number 
2020-004894-29 
Universal Trial Number 
Not applicable 
Other register number 
(ISRCTN, CT. gov…)  
Investigational New Drug 
Application Number 
152433 
Sponsor 
I.R.I.S.
International 
Coordinator 
Pr Alexander Karachunskiy 
Institute of Oncology, Radiology and Nuclear Medicine 
Dmitry Rogachev National Medical Research Center 
Moscow, Russia 
Date of the document 
2 December 2020 
Version of the document 
Final version 
CONFIDENTIAL 
Version No 
Final version date 
Countries concerned 
2.0 
2 Dec 2020 
INT 
Siège social - 50, rue Carnot - 92284 Suresnes cedex - France - Tél. 01.55.72.60.00 - www.servier.com
S.A.R.L. au capital de 7.895 euros • 319 416 756 RCS Nanterre
NCT04954326


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FOLLOW-UP OF VERSIONS 
Protocol No 
Substantial 
amendment 
No 
Final 
version date 
Countries 
concerned 
Nature of modifications 
1.0 
NA 
22 Oct 2020 
ALL 
Not Applicable 
2.0 
NA 
2 Dec 2020 
ALL 
Modifications were provided to 
the study protocol following 
FDA’s non-hold comments: 
-
Clarification 
about 
the
collection of PK and PAA
samples
-
Addition 
of 
an
immunogenicity timepoint
14 days post-dose (Day 17)
-
Clarification 
about 
the
sample size calculation
-
Addition of Ctrough 14 days
post-dose 
as 
a 
PK 
secondary endpoint 
-
Deletion 
of 
a 
specific
dosing regimen of 82.5 
U/kg for patients with low 
BSA 
-
Additional minor changes


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SYNOPSIS 
Name of the sponsor: 
I.R.I.S.
Name of Finished Product: 
Lyophilized pegaspargase 
Liquid pegaspargase 
Name of Active Ingredient: 
Pegaspargase  
S95014 
Oncaspar® 
Title of study: A multicentre, Phase II Randomized study, Open-label, with 2-arm Parallel Group, comparing 
the pharmacokinetics of the Liquid and the Lyophilized Formulations of pegaspargase (S95014) in Treatment 
of Paediatric Patients with Newly-Diagnosed Acute Lymphoblastic Leukemia (ALL) 
Study Brief Title: Pharmacokinetics comparability study of Liquid and Lyophilized pegaspargase (S95014) 
formulations in ALL 
Study Public Title: A study comparing the blood levels of both pegaspargase (S95014) formulations (liquid 
vs lyophilized) in the Treatment of Paediatric Patients with Acute Lymphoblastic Leukemia (ALL) 
Protocol No.: CL2-95014-002 
Coordinator, Investigators  
National coordinator and investigators: listed in a separate document 
Study centre(s): 
6-10 centres in Russia
Study period: 
­ Study duration for the participant: approximately 1.5 month
­ Study initiation date (planned date of first visit first participant):
Q1/Q2 2021 
­ Study completion date (planned date of last visit last participant):
Q2 2022 
Study development phase: II 
Objective(s):  
Primary objective: 
To compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations during the 
induction phase after a single IV dose in newly diagnosed paediatric patients with ALL  
Secondary objectives: 
­ To describe the PK of S95014 after administration of either lyophilized or liquid formulation
­ To evaluate the achievement of plasma asparaginase activity (PAA) of ≥0.1 U/mL after the administration
of either lyophilized or liquid S95014 
­ To assess the immunogenicity of both lyophilized and liquid S95014 formulations
­ To evaluate the safety profile through the occurrence of TEAEs including serious adverse events (SAEs),
regardless of causality and severity 
Methodology: 
This is a multicentre, randomized, open-label, phase II clinical study comparing the pharmacokinetics of 
lyophilized and liquid Pegaspargase (Oncaspar®, S95014) formulations in the treatment of newly diagnosed, 
untreated pediatric patients with ALL. 
Written informed consent and assent (when appropriate) will be obtained from each patient and/or his/her 
parent(s)/legal representative before initiation of study procedures. Patients will undergo screening after giving 
informed consent and will be included once all eligibility requirements for the study have been met.  
Baseline evaluations and risk stratification will be performed in compliance with the current ALL-MB 2015 


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Name of the sponsor: 
I.R.I.S.
Name of Finished Product: 
Lyophilized pegaspargase 
Liquid pegaspargase 
Name of Active Ingredient: 
Pegaspargase  
S95014 
Oncaspar® 
protocol. 
Each patient will be randomly assigned (1:1) to receive either lyophilized (arm 1) or liquid (arm 2) S95014 
intravenously over 1-hour at the dose of 2500 U/m² at Day 3 during the induction phase. Backbone 
chemotherapy agents will be administered as per ALL-MB 2015 protocol.  
The study duration will be approximately 1.5 month, including the screening (14 days) and the treatment 
period consisting of the induction phase (approximately 30 days). After completing the induction phase, 
patient will be discontinued from the study and, provided that the inclusion/non-inclusion criteria are fulfilled, 
will be proposed to enter a roll-over study for the consolidation phase, in compliance with ALL-MB 2015 
protocol. 
Eleven (11) sodium heparinised plasma for pharmacokinetic (serial PK samples) will be obtained, as follows: 
pre-dose, just after the end of infusion (on Day 3), 4 hours after the end of infusion (on Day 3), 24 hours after 
the end of infusion (on Day 4), 48 hours after the end of infusion (on Day 5), 120 hours (i.e. 5 days) after the 
end of infusion (on Day 8), 168 hours (i.e. 7 days) after the end of infusion (on Day 10), 216 hours (i.e. 9 days) 
after the end of infusion (on Day 12), 336 hours (i.e. 14 days) after the end of infusion (on Day 17), 432 hours 
(i.e. 18 days) after the end of infusion (on Day 21) and 600 hours (i.e. 25 days) after the end of infusion (on 
Day 28). 
Four (4) sodium heparinised plasma for asparaginase activity assessment will be obtained 7, 14, 18 and 25 
days after the administration of liquid or lyophilized S95014 (on Day 10, Day 17, Day 21 and Day 28). 
Samples collected for PAA assessment will be the same as for PK analysis to avoid duplicating sample 
collection. 
Three (3) sodium heparinised plasma for assessment of anti S95014 and anti-PEG antibodies will be obtained 
at pre-dose, 14 and 25 days after the infusion (i.e. on Day 17 and Day 28). 
All adverse events regardless of grade or causality will be collected after the informed consent is signed and 
during the entire treatment period.  
Number of included participants: 
Approximately 88 patients will be included to ensure 78 evaluable patients 
Diagnosis and main criteria for inclusion: 
Screening criteria 
-
Patients aged 1 to < 18 years
-
Patients with cytologically confirmed and documented newly diagnosed ALL according to NCCN
guidelines 2020 (see Appendix 2), excluding B-cell Burkitt ALL
-
Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 (see Appendix 3)
-
Highly effective contraception method
-
Signed informed consent and assent, when appropriate
Non-screening criteria: 
-
Unlikely to cooperate in the study
-
Pregnant and lactating women
-
Participation in another interventional study at the same time; participation in non-interventional
registries or epidemiological studies is allowed
-
Participant already enrolled in the study (informed consent signed)


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Name of the sponsor: 
I.R.I.S.
Name of Finished Product: 
Lyophilized pegaspargase 
Liquid pegaspargase 
Name of Active Ingredient: 
Pegaspargase  
S95014 
Oncaspar® 
-
Prior treatment with chemotherapy or radiotherapy (except steroids and intrathecal therapy)
-
Prior surgery or bone marrow transplant related to the studied disease
-
Down Syndrome
-
Psychiatric illness/social situation that would limit compliance with study requirements
-
Known history of pancreatitis
-
Known history of significant liver disease
-
Known carriers of HIV antibodies
-
Significant laboratory abnormality likely to jeopardize the patients’ safety or to interfere with the
conduct of the study, in the investigator’s opinion
-
Pre-existing known coagulopathy (e.g. haemophilia and known protein S deficiency)
-
History of previous or concurrent malignancy
-
History of sensitivity to polyethylene glycol (PEG) or PEG-based drugs
-
Severe or uncontrolled active acute or chronic infection
-
Uncontrolled intercurrent illness including life-threatening acute tumor lysis syndrome (e.g. with
renal failure), symptomatic congestive heart failure, cardiac arrhythmia
Inclusion criteria: 
Screening criteria must still be fulfilled at the time of the inclusion visit 
Non-inclusion criteria: 
Non-screening criteria must still be fulfilled at the time of the inclusion visit 
-
Women of childbearing potential tested positive in a serum pregnancy test within 7 days prior to
the treatment period
-
Inadequate hepatic function (bilirubin > 1.5 times upper limit of normal (ULN), transaminases > 5
x ULN)
-
Inadequate renal function defined as serum creatinine > 1.5 x ULN
Test drug: 
S95014 liquid (reference drug) and S95014 lyophilizate (test drug) are both IMPs 
­ Arm 1: lyophilized S95014 reconstituted will provide 5 mL of extractable volume with the concentration of
750 U/mL. The vial of lyophilized powder (3.750 U/vial) is reconstituted with 5.2 mL of SWFI to obtain a 
750 U/mL solution for single use. 
­ Arm 2: liquid S95014 is provided as 3.750 U per 5 mL solution in a single use vial to obtain a 750 U/mL
solution for single use. 
S95014 (either liquid or lyophilized) will be intravenously administered over 1 hour at the dose of 2500 U/m2 
at Day 3 of the induction phase. Patients will receive other backbone chemotherapy agents as per ALL-MB 
2015 protocol. 
Comparator: Liquid S95014 (reference drug) 
Duration of treatment:  
Screening period: up to 14 days 
Active treatment period: approximately 30 days 
Criteria for evaluation: 
Primary endpoint: 
Pharmacokinetics measurement: 
The following PK parameters will be determined: Area Under the Concentration-Time curve (AUC); 


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Name of the sponsor: 
I.R.I.S.
Name of Finished Product: 
Lyophilized pegaspargase 
Liquid pegaspargase 
Name of Active Ingredient: 
Pegaspargase  
S95014 
Oncaspar® 
maximum observed plasma asparaginase activity (Cmax). 
The above parameters will be calculated using non-compartmental analysis (NCA) approach based on 
observed plasma asparaginase activity (PAA) time profiles. These will be calculated for each patient and the 
corresponding descriptive statistics of PK parameters will be tabulated (arithmetic mean, SD, geometric mean, 
geometric CV, median, min, max). 
Statistical analysis of the primary endpoint (AUC and Cmax) will consist in an analysis of variance (ANOVA) 
and a 90% confidence interval for the ratios of the geometric means of PAA (after administration of 
lyophilized formulation)/ PAA (after administration of liquid formulation) will be calculated for Cmax and AUC 
using respective residual variances. 
The acceptance limits of the confidence intervals for geometric means ratios of asparaginase activity will be 
those defined in guidelines, i.e. [80.00%; 125.00%], to conclude that there is a comparability between one IV 
administration of lyophilized formulation versus one IV administration of liquid formulation 
Secondary endpoints: 
Pharmacokinetics measurements: 
Additional PK parameters from the ones defined as primary endpoint (e.g. Ctrough at 14 days post-dose, Tmax, 
T1/2) will be assessed. 
A statistical analysis will be performed on Ctrough, day 14 with an analysis of variance (ANOVA) and a 90% 
confidence interval for the ratios of the geometric mean for this parameter. 
Activity measurement:  
Plasma Asparaginase Activity (PAA) of ≥ 0.1 U/mL 7, 14, 18 and 25 days (i.e. Day 10, Day 17, Day 21 and 
Day 28) after the administration of either liquid or lyophilized S95014. 
Observed individual PAA level 7, 14, 18 and 25 days after administration of either liquid or lyophilized 
S95014 will be tabulated together with descriptive statistics (Arithmetic mean, SD, geometric mean, geometric 
CV, median, min, max). The number and proportion of patients achieving a PAA of ≥ 0.1 U/mL 7, 14, 18 and 
25 days after the administration of either liquid or lyophilized S95014 will be summarized. 
Immunogenicity measurements: 
Anti S95014 and anti-PEG antibodies will be assessed at pre-dose, 14 and 25 days after the S95014 infusion 
(i.e. Day 17 and Day 28). This evaluation will be based on qualitative enzyme-linked immunosorbent assay 
(ELISA) using S95014 as coating antigen. All positive samples will be further confirmed by competitive 
ELISA for the presence of binding antibodies against S95014. Samples, when confirmed positive, will then be 
assayed for the antibodies against PEG. The number and proportion of patients having anti S95014 ± anti-PEG 
antibodies 14 and 25 days (Day 17 and Day 28) after the administration of either liquid or lyophilized S95014 
will be summarized. 
Safety measurement: 
Safety assessments will be performed and reported throughout the study. This will include: 
­ adverse events (AEs), treatment emergent adverse events (TEAEs), adverse events of special interest
(AESI) assessments 
­ physical examinations, performance status
­ laboratory abnormalities assessment including haematology, blood biochemistry, urinalysis, coagulation
parameters 
­ vital signs measurements


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Name of the sponsor: 
I.R.I.S.
Name of Finished Product: 
Lyophilized pegaspargase 
Liquid pegaspargase 
Name of Active Ingredient: 
Pegaspargase  
S95014 
Oncaspar® 
­ Recording of any change or addition of a new concomitant treatment
Adverse events will be collected regardless of grade or IMP relationship and will be graded according to 
current NCI CTCAE criteria 5.0 
Safety analysis: descriptive summaries of demographic and baseline characteristics with a description of 
patient disposition and listing of medical history will be provided. The number and percentage of patients with 
adverse events will be tabulated by system organ class and preferred term. 
Determination of sample size: 
This study is a two-arm parallel 1:1 randomized trial to evaluate the PK comparability between liquid and 
lyophilized S95014 formulations. For both AUC and Cmax, the coefficient of variation (CoV) of 0.30 is 
assumed based on the estimation of CoV for liquid S95014 from a previous study (Angiolillo, 2014). 
Assuming a CoV of 0.30 and a true geometric mean ratio (GMR) of 100%, a total of 78 evaluable subjects (39 
subjects per arm) will provide approximately 90% power to establish the PK comparability. Assuming that 
10% of the included patients will not be evaluable (e.g. missing PK timepoint etc.), 88 subjects are expected to 
be included to allow 78 evaluable patients.  
Data Monitoring Committee: Not applicable 


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Contractual signatories 
I, the undersigned, have read the foregoing protocol and the “Participant information and consent form” 
document attached to the protocol and agree to conduct the study in compliance with such documents, Good 
Clinical Practice (GCP) and the applicable regulatory requirements. 
COORDINATOR/INVESTIGATOR: 
NAME 
CENTER NUMBER 
DATE 
SIGNATURE 
HEAD OF LATE STAGE AND LIFE CYCLE MANAGEMENT DEPARTMENT: 
NAME 
 
DATE 
SIGNATURE 
7 Dec 2020


S95014 
Amended clinical study protocol CL2-95014-002- Final version 
Other sponsor's signatories 
BIOSTATISTICS HEAD: 
NAME 
 
DATE 
{ 2-/~/7,-07,,--o 
SIGNATURE 
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Table of contents 
Table of contents ...................................................................................................................... 10 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 20 
2. BACKGROUND INFORMATION ................................................................................. 20 
2.1. Overview of disease epidemiology and current treatment ............................................. 20 
2.2. S95014 ............................................................................................................................ 20 
2.2.1. Mechanism of action of S95014 .................................................................................. 20 
2.2.2. S95014 pharmacokinetics ............................................................................................ 21 
2.2.3. Pegylated asparaginase development and status .......................................................... 21 
2.2.4. Development of a lyophilized S95014 formulation ..................................................... 22 
2.2.5. Study rationale and design ........................................................................................... 22 
3. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 23 
3.1. Primary objective ............................................................................................................ 23 
3.2. Secondary objectives ...................................................................................................... 23 
3.3. Exploratory objectives .................................................................................................... 23 
3.4. Endpoints ........................................................................................................................ 23 
4. STUDY DESIGN ............................................................................................................... 24 
4.1. Investigational plan......................................................................................................... 24 
4.1.1. Study plan ..................................................................................................................... 24 
4.1.2. Investigation schedule .................................................................................................. 25 
4.2. Measures to minimise bias ............................................................................................. 27 
4.3. Study products and blinding systems ............................................................................. 27 
4.3.1. Products administered .................................................................................................. 27 
4.3.2. IMP management ......................................................................................................... 28 
4.3.3. Management of blinding systems ................................................................................. 29 
4.4. Discontinuation of the study or temporary halt .............................................................. 29 
4.4.1. Premature discontinuation of the study or temporary halt ........................................... 29 
4.4.2. Premature discontinuation of the study in an investigator site (early site closure) ...... 30 
4.4.3. Discontinuation of the study in the event of objective reached ................................... 30 
4.5. Source data ..................................................................................................................... 30 
5. SCREENING AND WITHDRAWAL OF PARTICIPANTS ....................................... 30 
5.1. Screening criteria ............................................................................................................ 30 
5.1.1. Demographic characteristics ........................................................................................ 30 
5.1.2. Medical and therapeutic criteria ................................................................................... 30 
5.1.3. Informed consent .......................................................................................................... 31 
5.2. Non-screening criteria .................................................................................................... 31 
5.2.1. General criteria ............................................................................................................. 31 
5.2.2. Medical and therapeutic criteria ................................................................................... 31 
5.3. Inclusion criteria ............................................................................................................. 31 


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5.4. Non-inclusion criteria ..................................................................................................... 32 
5.4.1. General criteria ............................................................................................................. 32 
5.4.2. Medical and therapeutic criteria ................................................................................... 32 
5.5. Definition of women of childbearing potential and contraception methods .................. 32 
5.6. Retest management during screening period .................................................................. 32 
5.7. Additional information recorded at the inclusion visit ................................................... 32 
5.8. Participant withdrawal .................................................................................................... 33 
5.8.1. Withdrawal criteria ....................................................................................................... 33 
5.8.2. Procedure ...................................................................................................................... 33 
5.8.3. Lost to follow-up .......................................................................................................... 33 
6. TREATMENT OF PARTICIPANTS .............................................................................. 33 
6.1. IMPs and NIMPs administered....................................................................................... 33 
6.1.1. IMPs ............................................................................................................................. 33 
6.1.2. NIMPs .......................................................................................................................... 34 
6.2. IMP dispensing ............................................................................................................... 34 
6.3. Previous and concomitant treatments ............................................................................. 35 
6.4. IMP compliance .............................................................................................................. 35 
6.5. Discontinuation of the IMP ............................................................................................ 35 
7. ASSESSMENT OF PHARMACOKINETICS ............................................................... 35 
7.1. Methods and measurement times ................................................................................... 35 
8. ASSESSMENT OF SAFETY ........................................................................................... 37 
8.1. Specification of safety parameters .................................................................................. 37 
8.2. Methods and measurement times ................................................................................... 37 
8.3. Definition of Adverse events .......................................................................................... 39 
8.4. Definition of Serious adverse events .............................................................................. 40 
8.5. Definition of Overdose ................................................................................................... 40 
8.6. Definition of Adverse event of special interest .............................................................. 40 
8.6.1. Hepatotoxicity monitoring ........................................................................................... 41 
8.6.2. Pancreatitis monitoring ................................................................................................ 41 
8.6.3. Coagulopathy monitoring ............................................................................................. 41 
8.6.4. Hypersensitivity monitoring ......................................................................................... 42 
8.7. Definition of Events requiring an immediate notification (ERIN) ................................. 42 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) ...... 42 
8.9. Reporting procedures ...................................................................................................... 43 
8.9.1. Time frame for AE reporting ....................................................................................... 43 
8.9.2. Responsibilities of the investigator .............................................................................. 44 
8.9.2.1. 
Documentation of the event ..................................................................................... 44 
8.9.2.2. 
Follow-up of adverse events .................................................................................... 44 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP/NIMP a person around the 
participant) ............................................................................................................... 45 
8.9.2.4. 
Recording Methods in the e-CRF ............................................................................ 45 
8.9.2.5. 
Procedure for an event requiring an immediate notification ................................... 46 
8.9.3. Responsibilities of the sponsor ..................................................................................... 46 


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9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO
PHARMACOKINETICS OR SAFETY .......................................................................... 47 
9.1. Assessments related to screening/inclusion criteria ....................................................... 47 
9.2. Assessment of plasma asparaginase activity .................................................................. 47 
9.3. Assessment of immunogenicity ...................................................................................... 47 
9.4. Assessment of biomarkers .............................................................................................. 48 
10.
STATISTICS ................................................................................................................. 48 
10.1. Population ....................................................................................................................... 48 
10.1.1. Determination of sample size ....................................................................................... 48 
10.1.2. Analysis subset ............................................................................................................. 48 
10.2. Statistical analysis........................................................................................................... 49 
10.2.1. Pharmacokinetics analysis............................................................................................ 49 
10.2.2. Safety Analysis ............................................................................................................. 50 
10.2.2.1. Adverse Events ........................................................................................................ 50 
10.2.2.2. Other Safety Evaluations ......................................................................................... 50 
10.2.3. Analysis of Plasma Asparaginase Activity .................................................................. 51 
10.2.4. Population Analysis...................................................................................................... 51 
10.2.4.1. Subject Disposition .................................................................................................. 51 
10.2.4.2. Demographic and Baseline Characteristics ............................................................. 51 
10.2.4.3. Concomitant Medication ......................................................................................... 51 
10.2.5. Immunogenicity Analysis ............................................................................................ 51 
10.3. Handling of Missing, Unused, and Spurious Data ......................................................... 52 
10.4. Planned Interim Analysis................................................................................................ 52 
10.5. Procedures for Reporting Changes to the Planned Analysis .......................................... 52 
11.
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ...................................... 53 
12.
QUALITY CONTROL AND QUALITY ASSURANCE.......................................... 53 
12.1. Study monitoring ............................................................................................................ 53 
12.1.1. Before the study ........................................................................................................... 53 
12.1.2. During the study ........................................................................................................... 53 
12.2. Computerised medical file .............................................................................................. 54 
12.3. Audit - Inspection ........................................................................................................... 55 
13.
ETHICS ......................................................................................................................... 55 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 55 
13.2. Study conduct ................................................................................................................. 55 
13.3. Participant information and informed consent ............................................................... 56 
13.4. Modification of the information and consent form ........................................................ 57 
14.
DATA HANDLING AND RECORD KEEPING ...................................................... 57 
14.1. Study data ....................................................................................................................... 57 
14.2. Data management ........................................................................................................... 58 
14.3. Archiving ........................................................................................................................ 59 


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15.
INSURANCE ................................................................................................................ 59 
16.
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND
PUBLICATION POLICY ................................................................................................ 59 
17.
ADMINISTRATIVE CLAUSES ................................................................................. 60 
17.1. Concerning the sponsor and the investigator .................................................................. 60 
17.1.1. Persons to inform ......................................................................................................... 60 
17.1.2. Substantial protocol amendment and amended protocol.............................................. 60 
17.1.3. Final study report ......................................................................................................... 61 
17.2. Concerning the sponsor .................................................................................................. 61 
17.3. Concerning the investigator ............................................................................................ 62 
17.3.1. Confidentiality - Use of information ............................................................................ 62 
17.3.2. Organisation of the centre ............................................................................................ 62 
17.3.3. Documentation supplied to the sponsor ....................................................................... 62 
18.
REFERENCES ............................................................................................................. 63 
19.
APPENDICES ............................................................................................................... 64 


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List of tables 
Table (3.4) 1 - Endpoints ................................................................................................................... 23 
Table (4.1.2) 1 - Investigation schedule ............................................................................................. 26 
Table (4.3.1) 1 – Description of the IMPs (both S95014 formulations) ............................................ 27 
Table (4.3.1) 2 – Description of S95014 packaging .......................................................................... 28 
Table (8.2) 1 - Local Clinical laboratory parameters collection plan ................................................ 38 


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List of figures 
Figure (4.1.1) 1 – Study plan ............................................................................................................. 25 


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List of appendices 
Appendix 1: ALL-MB 2015 protocol ................................................................................................ 64 
Appendix 2: NCCN guidelines 2020 ................................................................................................. 64 
Appendix 3: Patient performance status ............................................................................................ 64 
Appendix 4: Hepatotoxicity form ...................................................................................................... 64 
Appendix 5: Trial Conduct During National or International Public Health Emergency ................. 64 
Appendix 6: World Medical Association Declaration of Helsinki .................................................... 64 
Appendix 7: Instructions to investigator for handling data rights requests ....................................... 64 


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List of abbreviations 
ADA 
: Anti-Drug Antibodies 
ADL 
: Activities of Daily Living 
AE 
: Adverse Event 
AEOSI 
: Adverse Event Of Special Interest 
ALL 
: Acute Lymphoblastic Leukemia 
ALP 
: Alkaline Phosphatase 
ALT 
: ALanine aminoTransferase 
ANOVA 
: Analysis of Variance 
APTT 
: Activated Partial Thromboplastin Time 
AST 
: ASpartate aminoTransferase 
AUC 
: Area Under the Curve 
BFM 
: Berlin-Frankfurt-Munster 
BMI 
: Body Mass Index 
BP 
: Blood Pressure 
bpm 
: beats per minute (heart rate unit) 
BSA 
: Body Surface Area 
BUN 
: Blood Urea Nitrogen 
CBI 
: Central Business Intelligence 
CHMP 
: Committee for Medical Products for Human Use 
CI 
: Confidence Interval 
cm 
: centimetre 
Cmax 
: maximum Concentration 
Ctrough, day 14 
: Lowest concentration reached by a drug 14 days after the 
administration 
CMP 
: Clinical Monitoring Plan 
CISO 
: Chief Information Security Officer 
COG 
: Children’s Oncology Group 
CoV 
: Coefficient of Variation 
CRA 
: Clinical Research Associate 
CRF 
: Case Report Form 
CRO 
: Contract Research Organisation 
CSR 
: Clinical Study Report 
CT 
: Computerized Tomography 
CTCAE 
: Common Terminology Criteria for Adverse Events 
CV 
: Curriculum Vitae 
DAP 
: Data Analysis Plan 
DPO 
: Data Protection Officer 
ECG 
: ElectroCardioGram 
ECOG 
: Easter Cooperative Oncology Group 
eCRF 
: Electronic Case Report Form 
EEA 
: European Economic Area 
e.g.
: Exempli gratia (for example) 
ELISA
: Enzyme-Linked Immunosorbent Assays 
EMA
: European Medicines Agency 
ERIN
: Event Requiring Immediate Notification 


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EU 
: European Union 
FAS 
: Full Analysis Set 
FDP 
: Fibrin Degradation Product 
g 
: gram 
G/L 
: Giga (109) per litre 
GCP 
: Good Clinical Practice 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl 
Transpeptidase) 
GMR 
: Geometric Mean Ratio 
h 
: hour 
HBs 
: Surface antigen of Hepatitis B virus 
HCV 
: Hepatitis C virus 
HDL 
: High-Density Lipoprotein 
HEV 
: Hepatitis E virus 
HIV 
: Human Immunodeficiency Virus 
HR 
: Heart Rate 
I.R.I.S.
: Institut de Recherches Internationales Servier 
ICF
: Informed Consent Form 
ICH
: International Conference on Harmonisation 
ICTR
: International Centre for Therapeutic Research 
i.e.
: id est (that is) 
IEC 
: Independent Ethics Committee 
IM 
: Intra Muscular 
IMP 
: Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial (test drug / placebo / reference product) 
INR 
: International Normalized Ratio 
IRS 
: Interactive Response System 
IV 
: IntraVenous (route) 
kg 
: kilogram 
L 
: Litre 
LDH 
: Lactate DeHydrogenase 
LDL 
: Low-Density Lipoprotein 
LFT 
: Liver Function Test 
LVEF 
: Left Ventricular Ejection Fraction 
MAH 
: Marketing Authorization Holder 
MedDRA 
: Medical Dictionary for Regulatory Activities 
MRI 
: Magnetic Resonance Imaging 
MUGA scan 
: Multi-Gated Acquisition scan 
NASH 
: Non-Alcoholic SteatoHepatitis 
NCCN 
: National Comprehensive Cancer Network 
NCA 
: Non-Compartmental Analysis 
NCI 
: National Cancer Institute 
NGO 
: Non-Governmental Organization 
NIMP 
: Non-Investigational Medicinal Product (backbone regimen used 
in the frame of ALL-MB 2015 protocol) 
µmol 
: micromole 
mg 
: milligram 


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min 
: minute 
mL 
: millilitre 
NA 
: Not Applicable 
PAA 
: Plasma Asparaginase Activity 
PBS 
: Phosphate-Buffered Saline 
PCR 
: Polymerase Chain Reaction 
PEG 
: PolyEthylene Glycol 
PD 
: PharmacoDynamics 
PK 
: PharmacoKinetics 
PKAS 
: Pharmacokinetic Analysis Set 
PS 
: Performance Status 
PT 
: Prothrombin Time 
RBC 
: Red Blood Cells 
RMP 
: Risk Management Plan 
RNA 
: Ribonucleic Acid 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SAS 
: Safety Analysis Set 
SD 
: Standard Deviation 
sec 
: second 
SmPC 
: Summary of Product Characteristics 
SWFI 
: Sterile Water for Injection 
t½z 
: terminal half-life 
TEAE 
: Treatment Emergent Adverse Event 
test drug 
: Drug substance in a given dosage form, tested in a clinical trial. 
In this study, it corresponds to the lyophilized S95014  
Tmax 
: time corresponding to Cmax 
TSH 
: Thyroid Stimulating Hormon 
U 
: Unit 
ULN 
: Upper Limit of reference range 
US 
: United States 
V 
: Visit 
WBC 
: White Blood Cells 
WHO-Drug 
: World Health Organization Drug Dictionary 
WOCBP 
: Woman of Child Bearing Potential 


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1. ADMINISTRATIVE STRUCTURE OF THE STUDY
Non sponsor parties, sponsor parties and CRO responsible for local management of the study are 
described in a separate document entitled Administrative part of clinical study protocol. 
The list of investigators is described in a separate document attached to the protocol and entitled 
"List of investigators".  
2. BACKGROUND INFORMATION
2.1. Overview of disease epidemiology and current treatment 
Leukemia is the most common pediatric malignancy. Acute lymphoblastic leukemia (ALL) is 
typically characterized by the proliferation of large number of immature lymphoid cells in the bone 
marrow, peripheral blood and other organs. ALL is the most common type (46.6%) of acute 
leukemia in childhood and the most commonly diagnosed cancer in children (25%) 
(Esparza, 2005; Noone et al, 2018). Approximately 1000 children are newly diagnosed with 
ALL each year in Russia (Kaprin, 2019).  
The treatment of ALL includes long-term use of multiagent chemotherapy (National 
Comprehensive Cancer Network clinical practice guidelines), of which asparaginase is a 
cornerstone component (Hoelzer D et al, 2016, Asselin B et al, 1999). Asparagine is a nonessential 
amino acid for normal cell growth but is considered essential for leukaemic cells as these cells are 
dependent on exogenous sources of asparagine for survival. Asparaginase selectively kills 
leukaemic cells by depleting asparagine levels. (Asselin B et al, 1999). Native Escherichia coli-
derived L-asparaginase (E. coli L-asparaginase) is one of the asparaginase preparations that have 
been used for the treatment of ALL since 1970s; however, its use is associated with high 
immunogenicity, which can be manifested by the occurrence of hypersensitivity reactions 
(Silverman LB et al, 2010) and/or the neutralization of asparaginase activity without any signs of 
hypersensitivity (i.e. silent inactivation) (Tong WH et al, 2014). Moreover, E. coli L-asparaginase 
must be administered frequently (i.e. three times weekly), as the drug has a very short elimination 
half-life (Asselin B et al, 1999). 
Consequent to these limitations, pegylated formulations of E. coli L-asparaginase have been 
developed, including pegaspargase (Oncaspar®) [with a succinimidyl succinate linker]. 
The worldwide standard treatments for pediatric ALL include the treatment protocols established by 
the Children’s Oncology Group (COG) and the Berlin-Frankfurt-Munster (BFM) group. In Russia, 
approximately 90% of newly-diagnosed pediatric patients with ALL are treated in compliance with 
the ALL-MB 2015 protocol (see Appendix 1).  
2.2. S95014 
Detailed information on the nonclinical and clinical experience with S95014 is provided in the 
latest version of the Investigator’s Brochure. 
2.2.1. 
Mechanism of action of S95014 
The mechanism of action of L asparaginase is the enzymatic cleavage of the amino acid asparagine 
into aspartic acid and ammonia, with subsequent depletion of asparagine in the blood plasma. Since 


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lymphoblastic tumor cells, unlike healthy cells, appear to be unable to synthetize asparagine, the 
asparagine depletion results in inhibition of cell protein synthesis and therefore in their destruction. 
Hence, when plasma levels of L-asparagine decrease, intracellular levels of L-asparagine become 
markedly low, protein synthesis is inhibited, and leukemic cells undergo apoptosis. Unless an 
extracellular supply of L-asparagine is available, L-asparaginase is a specific chemotherapeutic 
agent for leukemic cells while preserving non-leukemia cells. The goal of asparaginase therapy is 
sustained systemic depletion of asparagine.  
2.2.2. 
S95014 pharmacokinetics 
Pharmacokinetic assessments of S95014 were based on an enzymatic assay measuring asparaginase 
activity after IM (CCG-1962 study) and IV (AALL07P4, DFCI 11-001 studies) administration.  
In study AALL07P4, following a single 2500 U/m² IV dose of S95014 during the induction phase, a 
Cmax of 1.6 U/mL is reached in 1.25 hour; the area under the asparaginase activity time curve 
(AUC) from time zero to infinity (AUCinf) is 16.6 U/mL/day. Also, 95.3% of ALL patients 
sustained asparaginase activity ≥ 0.1 U/mL for 18 days (Angiolillo, 2014). 
After single and repeated 2500 U/m2 doses of S95014, clinically relevant asparaginase activity is 
maintained over the entire dosing interval of two weeks. In study DFCI 11-001, following a single 
dose of IV S95014 at 2500 U/m2 during the induction phase, 93.5% of ALL patients sustained 
asparaginase activity ≥ 0.1 U/mL for 18 days. Furthermore, following biweekly dosing of IV 
S95014 during the post-induction phase, a nadir asparaginase activity of > 0.4 U/mL is seen in all 
patients from weeks 7–25 (Vrooman, 2019). 
For more details please refer to the last version of the Investigator’s Brochure. 
2.2.3. 
Pegylated asparaginase development and status 
Oncaspar® (pegaspargase; S95014) is a variation of the enzyme L-asparaginase modified by 
covalently bonding units of monomethoxy polyethylene glycol (PEG) to the enzyme, forming the 
active pharmaceutical ingredient PEG-L-asparaginase.  
In the United States (US), S95014 received approval in 1994 for second-line use in acute 
lymphoblastic leukaemia (ALL) following the development of hypersensitivity to native L-
asparaginase. In 2006, the US authorization of S95014 was expanded to include first-line treatment 
of ALL.  
Pegaspargase is now very well established in clinical practice in the first-line treatment of ALL and 
is licensed in many countries (Heo YA et al, 2019). It has been determined by the World Health 
Organization (WHO) an essential medication needed to meet the needs of a health system and is 
included in the List of Essential Medicines (WHO 2019). 
The safety profile of pegaspargase has also been well characterized over these last 25 years of 
consistent use in ALL treatment protocols. The most common (>5%) grade ≥3 AEs included 
hepatotoxicity (elevated transaminases, increased bilirubin and hypoalbuminemia), febrile 
neutropenia, hypertriglyceridemia, hyperglycemia, pancreatitis, coagulopathy, embolic and 
thrombotic events, and hypersensitivity. For further details, please refer to the last version of the 
Investigator’s Brochure. 
So far, S95014 is not approved yet in Russia and the product is only available through a non-
governmental organization (NGO) special request. Thus, patients treated in ALL-MB 2015 protocol 


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are administered S95014 during the induction phase (one dose) and native L-asparaginase during 
the consolidation phase. Once approved, S95014 is expected to play an important role in Russia as a 
first-line treatment for ALL. 
2.2.4. 
Development of a lyophilized S95014 formulation 
Different formulations containing different quantitative and qualitative compositions of 
cryoprotectants were investigated to identify the best product composition that could withstand the 
lyophilization process and guarantee the production of high-quality drug product with improved 
stability. The lyophilized S95014 powder for Injection is provided in a single-use vial which after 
reconstituted will contain 3,750 U/5mL of active PEGylated L-asparaginase [750 U/mL after 
reconstitution with 5.2 mL of sterile water for injection (SWFI)], which is equivalent to the strength 
of liquid S95014. The lyophilized S95014 formulation has a longer shelf-life as compared to the 
liquid formulation (36 months vs 8 months). 
A comparative, single-dose and 4-week repeat dose, pharmacokinetic and pharmacodynamic 
preclinical study of IV administered liquid and lyophilized S95014 formulations was performed in 
dogs. In this study, lyophilized S95014 has been demonstrated to be equivalent to the original liquid 
S95014.  
S95014 liquid formulation had been authorized by centralized review procedures in 28 countries in 
the European Union (EU) and 3 countries in the European Economic Area (EEA) in first line 
treatment 
of 
ALL 
in 
2016. 
The 
lyophilized 
formulation 
of 
S95014 
demonstrated 
pharmacokinetic/pharmacodynamic comparability through comprehensive analytical and non-
clinical comparability assessment recommended by the Committee for Medical Products for Human 
Use (CHMP) of the European Medicines Agency (EMA). Consequently, the use of lyophilized 
formulation for S95014 was approved by centralized review procedures in 28 countries in the EU 
and 3 countries in the EEA in 2017. 
2.2.5. 
Study rationale and design 
This phase II, parallel, open-label single dose pharmacokinetics (PK) study aims to demonstrate the 
pharmacokinetic comparability of both liquid and lyophilized S95014 formulations in newly-
diagnosed paediatric ALL patients.  
S95014 will be intravenously administered at the labelled dose of 2500 U/m², during the induction 
phase, in at least 78 paediatric patients. Patients will receive other backbone chemotherapeutic 
regimen as per ALL-MB 2015 protocol (see Appendix 1).  
Lyophilized S95014 formulation is widely used in many European countries since its approval in 
2017. Moreover, the review of the safety information from post-marketing setting globally has not 
revealed any noticeable differences between the two presentations. For further details about the 
risks of lyophilized S95014 administration, please refer to the latest version of the Investigator’s 
Brochure. 
The study will be conducted in compliance with the protocol, GCP, the ethical principles that have 
their origin in the Declaration of Helsinki and the applicable regulatory requirements. 


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3.
STUDY OBJECTIVES AND ENDPOINTS
3.1. Primary objective 
To compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations during 
the induction phase after a single IV dose in newly diagnosed paediatric patients with ALL  
3.2. Secondary objectives 
­ To describe the PK of S95014 after administration of either lyophilized or liquid formulation 
­ To evaluate the occurrence of treatment emergent adverse events (TEAEs) including serious 
adverse events (SAEs), regardless of causality and severity, based on National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 
­ To evaluate the achievement of plasma asparaginase activity (PAA) of ≥0.1 U/mL after the 
administration of either lyophilized or liquid S95014  
­ To assess the immunogenicity of both lyophilized and liquid S95014 formulations  
3.3. Exploratory objectives 
Not applicable 
3.4. Endpoints  
Table (3.4) 1 - Endpoints 
Objectives 
Endpoints 
Primary 
To compare the PK of both lyophilized and liquid 
S95014 formulations during the induction phase 
after a single IV dose (2500 U/m²) in newly 
diagnosed paediatric patients with ALL  
 
PK parameters of S95014 in plasma (Cmax, AUC) 
Secondary 
-
To describe the PK of S95014 after
administration of either lyophilized or 
liquid formulation  
-
To evaluate the achievement of PAA of
≥0.1 U/mL after the administration of
either lyophilized or liquid S95014
-
To assess the immunogenicity of both
lyophilized 
and 
liquid 
S95014
formulations
-
To evaluate the occurrence of TEAEs
including SAEs, regardless of causality
and severity, based on NCI CTCAE 5.0
Additional PK parameters from the ones defined 
as primary endpoints (e.g. Ctrough 14 days post-
dose, Tmax, T1/2)  
PAA on Day 10, Day 17, Day 21 and Day 28 of 
induction (7, 14, 18- and 25-days post dose) 
Anti S95014 ± anti-PEG antibodies at pre-dose, 
14 days and 25 days post dose 
Safety tolerance profile of S95014 assessed by 
incidence and severity of AEs and SAEs 
-
Laboratory 
tests: 
haematology 
with
differential, 
blood 
biochemistry,
coagulation, urinalysis, hepatitis markers
and pregnancy test
-
vital signs and performance status
Please refer to section 7, 8, and 9 for further details. 


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4.
STUDY DESIGN
4.1. Investigational plan 
4.1.1. 
Study plan 
This is a multicentre, national, randomized, open-label, phase II clinical study comparing the 
pharmacokinetics of lyophilized and liquid Pegaspargase (Oncaspar®, S95014) formulations in the 
treatment of newly diagnosed, untreated pediatric patients with ALL. Considering the risk of 
immunogenicity and hypersensitivity with S95014, it was decided to conduct a parallel study. 
Written informed consent and assent (when appropriate) will be obtained from each patient and/or 
his/her parent(s)/legal representative before initiation of study procedures (see section 13.3). 
Patients will undergo screening after giving informed consent and will be included once all 
eligibility requirements for the study have been met. Baseline evaluations and risk stratification will 
be performed in compliance with the current ALL-MB 2015 protocol.  
Each patient will be randomly assigned (1:1) to either lyophilized (arm 1) or liquid (arm 2) S95014 
intravenously at the dose of 2500 U/m² at Day 3, in combination with other backbone chemotherapy 
agents as per local practice (see Appendix 1).  
The study duration will be approximately 1.5 month, including the screening (14 days) and the 
treatment period consisting of the induction phase (approximately 30 days). After completing the 
induction phase, patient will be discontinued from the study and, provided that the inclusion/non-
inclusion criteria are fulfilled, will be proposed to enter into a roll-over study (CL2-95014-003) for 
the consolidation phase. 
For more details about the statistical analyses and the sample size calculation please refer to the 
Section 10. 
The study plan is shown in Figure (4.1.1) 1. 
In case of non-inclusion of a participant, it is the investigator’s responsibility to ensure, in 
accordance with the local standards of care and medical practices that:  
­ The reason of non-inclusion is explained to the participant, 
­ Any event associated with any procedure/condition required by the study protocol (e.g. an event 
occurring following the discontinuation of a forbidden treatment) is collected, 
­ An adequate alternative medical care is proposed to the participant. 
A non-inclusion visit is not mandatorily carried out, provided these requirements are met and 
documented in the medical file of the participant. 


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Figure (4.1.1) 1 – Study plan 
The study will be divided into the following periods for each participant: 
­ Screening visit (up to 14 days prior to inclusion): to obtain informed consent and check the 
screening/non-screening criteria. 
­ Screening period (Day -14 to Day -1): to check the eligibility of the patient to be included and 
randomized in the study within 14 days prior to the inclusion. 
­ Inclusion visit (Day 0): to check inclusion/non-inclusion criteria and to confirm inclusion of the 
patient in the study 
­ Randomization (Day 3): the day of S95014 infusion (i.e. Day 3), included patients will be 
randomly assigned to one of the two treatment groups: 
Lyophilized S95014 (arm 1)
Liquid S95014 (arm 2)
­ Treatment period: treatment period will start from the day of S95014 infusion, corresponding 
to Day 3 of the induction phase, until the withdrawal/end-of-study visit.  
­ Withdrawal/End-of-study visit: at least 30 days after S95014 infusion (i.e. Day 33) and before 
starting the consolidation phase. During the withdrawal/end-of-study visit, patients will be 
proposed to participate in a roll-over study (CL2-95014-003) for the consolidation phase using 
lyophilized S95014 in combination with backbone regimen as per ALL-MB 2015 protocol. 
The study start is defined as the date of the first visit of the first participant. 
End of Trial is defined as the date of the last visit of the last participant. 
4.1.2. 
Investigation schedule 
Table (4.1.2) 1 describes the measurement of efficacy and safety assessed during the study 


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Table (4.1.2) 1 - Investigation schedule 
Screening 
visit 
Screening period – Inclusion 
Induction phase 
Withdrawal/ End-of-study 
visit 
D3 
D4 
D5 
D8 D10 D12 D17 D21 D24 D28 
Informed consent 
X 
Screening criteria  
X 
Height / Weight / BSA 
X 
X 
Inclusion / exclusion criteria  
X 
Relevant 
medical 
/ 
surgical 
history 
X 
Previous treatments 
X 
Concomitant treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 
X 
X 
IRS randomization 
X 
S95014 administration 
X (see section 6.1) 
NIMP administration 
See Appendix 1 
Pharmacokinetic assessment 
Blood samples 
X pre-dose, just after the infusion, 4h after the 
end of infusion 
X  
24h after the end of infusion 
X 
48h after the end of infusion 
X 
X 
X 
X 
X 
X 
Pharmacodynamic assessment 
Plasma Asparaginase Activity 
X2 
X2 
X2 
X2 
Immunogenicity assessment 
Blood samples 
X pre-dose 
X 
X 
Safety assessments 
Vital signs 
X 
X pre-dose, post-infusion 
X 
Physical examination / ECOG  
X 
X pre-dose, post-infusion 
X 
ECG 
X 
X (see section 8.2) 
X 
Cardiac imaging1 
X 
X 
Adverse events  
X 
X 
X 
Laboratory examinations 
Blood haematology 
X 
X  
X 
X 
X 
X 
Blood biochemistry 
X 
X  
X 
X 
X 
X 
Blood coagulation 
X 
X  
X 
X 
X 
X 
Urinary biochemistry 
X 
X  
X 
X 
X 
X 
Hepatitis serology 
X 
X 
1 If echocardiography is performed within 14 days before signed consent, results could be used to assess patient’s inclusion in order to avoid unnecessary exam 
2 Samples collected for PAA assessment will be the same as for PK assessment to avoid duplicating sample collection 
 


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For further practical details, methods of measurement are provided in sections 7, 8 and 9. 
The maximum total volume of blood collected per participant during the study will be 200 
mL. Additional blood samples will be collected in the frame of the ALL-MB 2015 protocol, 
as per local practice.  
4.2. Measures to minimise bias 
This is a multicentre, randomized, open-label study. Subjects will be randomized to the liquid 
and lyophilized formulations according to a 1:1 ratio. The randomization will not be adaptive. 
No stratification factor will be used during randomization. The randomization will be 
centralized with an Interactive Response System (IRS). 
During the study, pharmacokinetics, PAA and immunogenicity analysis will be performed in 
a specific central laboratory which will minimise the variability of measurements. 
4.3. Study products and blinding systems 
4.3.1. 
Products administered 
S95014 liquid (reference drug) and S95014 lyophilizate (test drug) are both IMPs and will be 
manufactured under the responsibility of Les Laboratoires Servier Industrie (Gidy, France). 
Currently, S95014 is not authorized in Russia in any of its formulations. 
Table (4.3.1) 1 provides a description of the IMPs. 
Table (4.3.1) 1 – Description of the IMPs (both S95014 formulations) 
S95014 
Liquid 
S95014 
Lyophilizate 
Pharmaceutical form 
Solution for infusion 
Powder for solution for infusion 
Unit dosage 
3750 U /5 ml vial 
3750 U /5 ml vial 
Appearance, colour 
Colourless solution 
Lyophilized drug product: White to off 
white cake  
Reconstituted drug product: Colourless 
solution 
Composition (Component/ 
Amount per mL/ Function) 
Each vial contains 750 U S95014 
active ingredient per mL, monobasic 
sodium phosphate and dibasic sodium 
phosphate as buffering agent, sodium 
chloride for tonicity and water for 
injections QS to 1 ml as solvent 
Each vial contains 4050 U S95014 active 
ingredient, 
sucrose 
as 
lyoprotectant, 
sodium phosphate monobasic and dibasic 
as buffering agents, sodium chloride for 
tonicity, 
sodium 
hydroxide 
and 
hydrochloric acid for PH adjustment. 
After reconstitution with 5.2 ml SWFI the 
vial contains 750 U / ml or 3750 / 5ml 
S95014 active ingredient 
Table (4.3.1) 2 provides a description of the packaging of the IMPs. 


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Table (4.3.1) 2 – Description of S95014 packaging 
Number of units of the pharmaceutical form per 
primary packaging 
-
3750 U S95014 /5 mL solution for infusion
in an individual clear glass vial
-
4050 U of S95014 powder for solution for
infusion in an individual clear glass vial
Number of primary packaging per secondary 
packaging 
1 vial of S95014 liquid per box 
1 vial of S95014 lyophilizate per box 
Number of secondary packaging per patient and per 
treatment period 
The number of vials per patient will depend on the 
patient’s BSA 
The labelling of packages complies with the regulatory requirements of the country involved 
in the study. 
Backbone therapy drugs will be administered as per ALL MB 2015 protocol (see Appendix 
1). They will be regarded as NIMPs and will not be provided by the Sponsor. For further 
information about the NIMPs, please refer to section 6.1.2. 
4.3.2. 
IMP management 
S95014 liquid (reference drug) and S95014 lyophilizate (test drug) are both IMPs and will be 
manufactured under the responsibility of Les Laboratoires Servier Industrie (Gidy, France). 
IMP receipt, dispensing according to the experimental design of the study (for the description 
of dispensing methods, refer to section 6.2), accountability and collection are the 
responsibility of the investigator and/or pharmacist of the medical institution. 
IMP receipt and dispensing will be managed through an IRS. 
Specific handling conditions and cleaning procedures will be described in the Pharmacy 
Manual. 
Stability and storage 
The IMP should be stored in a secure area with restricted access. Specific storage conditions 
are mentioned on IMP labelling and are detailed in the Investigator’s Brochure. 
The investigator/pharmacist is responsible for the IMP temperature monitoring daily using 
FONT-CIRT-FORM-311 “Therapeutic Unit temperature log sheet - centre” (recording Min-
Max temperature every working day) or an equivalent document.  
In case of temperature deviation, the investigator/pharmacist should immediately: 
­ block the IRS for the concerned IMPs and place them in quarantine,  
­ alert the monitor or the local project manager if the monitor is absent, forward him all 
needed information and implement the instructions received. 
Furthermore, the investigator/pharmacist must put in place an adequate corrective/preventive 
action once the first temperature deviation occurs in order to avoid recurrence. 
IMP management will be verified on a regular basis by the study monitor. 
The investigator and/or the pharmacist of the medical institution and/or a designated person 
from their study team must complete in real time all the documents provided by the sponsor 
concerning IMP management (therapeutic unit tracking form or an equivalent document…). 
Therapeutic unit tracking form, or an equivalent document, is the source document to fulfil. 


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The investigator and/or the pharmacist of the medical institution should only use the IMP 
provided for the participants involved in the study. 
All defects or deterioration of IMPs or their packaging are to be reported to the study monitor, 
and to the IRS. The investigator will notify the monitor of all complaints set out by a 
participant (appearance…). 
In the event of anticipated return of IMPs to the sponsor (batch recall), the sponsor will 
prepare an information letter intended for the investigator and/or pharmacist of the medical 
institution. This letter will be sent by the person locally responsible for the study to each study 
centre. On receipt of the letter, the investigator and/or the pharmacist will verify the presence 
of the IMP on site at the moment the incident becomes known, by using, among other tools, 
the therapeutic unit tracking form, or an equivalent document. 
Destruction 
Destruction of the IMP is the responsibility of the sponsor and/or the investigator and/or the 
pharmacist of the medical institution. 
Used remaining treatments will be locally destroyed and unused IMPs will subsequently be 
collected and stored according to the local procedures and requirements, by the person 
responsible for the IMP management. 
A certificated destruction for unused IMPs will be performed according to standard modalities 
for that class of product and the attestation must be sent to the sponsor. The practical 
procedures for destruction of unused IMP will be defined by the sponsor and adapted to the 
centre. An IMP collection and destruction form will be completed before the shipment of IMP 
to destruction. Destruction of IMP may be possible when the product has been used, has 
expired or after at least the last visit of the last treated participant. 
4.3.3. 
Management of blinding systems  
Not applicable 
4.4. Discontinuation of the study or temporary halt 
4.4.1. 
Premature discontinuation of the study or temporary halt 
This study may be temporarily halted or prematurely discontinued at any time for any 
sufficient reasonable cause. 
After having informed the national coordinator, the sponsor or the Independent Ethics 
Committee (IEC) or the Competent Authority may terminate the study before its scheduled 
term. Two copies of the written confirmation will be dated and signed by the national 
coordinator. The IEC and Competent Authority will be informed according to local 
regulations. 
If the study is prematurely discontinued, the on-going participants should be seen as soon as 
possible, and the same assessments as described in section 5.8 should be performed.  


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Under some circumstances, the investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the 
participant’s interests.  
In case of study suspension (temporary halt), the study may resume once concerns about 
safety, protocol compliance, data quality are addressed and satisfy the Sponsor, the 
Independent Ethics Committee (IEC) and Competent Authority. 
4.4.2. 
Premature discontinuation of the study in an investigator site (early site closure) 
The sponsor reserves the right to close a study site at any time for any sufficient reasonable 
cause at the sole discretion of the sponsor.  
The investigator may also initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
­ Failure of the investigator to comply with the protocol, the requirements of the IEC or local 
Competent Authorities, the sponsor's procedures, or GCP guidelines 
­ inadequate recruitment of participants by the investigator 
­ Discontinuation of further study intervention development 
The IEC(s) and Competent Authorities will be informed according to local regulations. 
4.4.3. 
Discontinuation of the study in the event of objective reached 
Not applicable 
4.5. Source data 
Patient’s medical file (e.g. ECG report, clinical laboratory examination’s reports and all other 
patients’ examination results), PK requisition forms will be considered as source documents. 
Source data and source documents of the centre should be clearly identified in a specific, 
detailed and signed document before the beginning of the study. 
5.
SCREENING AND WITHDRAWAL OF PARTICIPANTS
5.1. Screening criteria 
5.1.1. 
Demographic characteristics 
1. Male or female patient aged ≥ 1 to < 18 years
5.1.2. 
Medical and therapeutic criteria 
2. Patients with cytologically confirmed and documented newly diagnosed ALL 
according to NCCN guidelines 2020 (see Appendix 2), excluding B-cell Burkitt ALL
3. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2
4. Women of childbearing potential (WOCBP) must use a highly effective method of 
birth control (both described in section 5.5) during study treatment and for 6 months 
after the last dose of IMP. In case of use of oral contraception women should have


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been stable on the same contraceptive drug (i.e. same active principle) for at least 1 
month prior to the first IMP administration. In case of use of hormonal contraception, 
WOCBP and male participants with WOCBP partners should use a second method of 
contraception, also called barrier method, such as male or female condoms, cap, 
diaphragm or sponge with spermicide. However, since there is a potential for an 
indirect interaction between S95014 and oral contraceptives, the concomitant use of 
S95014 and oral contraceptives is not recommended. A method other than oral 
contraceptives should be used in WOCBP. 
5. Male participants with WOCBP partners must use a condom during the study and until
at least 6 months after the last dose of IMP. In addition, contraception should be
considered for their female partners. Contraceptive measures do not apply if the
participant is sterile, vasectomized or sexually abstinent. Sperm donation will not be
allowed during the study and for 6 months after the last dose of IMP.
5.1.3. 
Informed consent 
Obtained as described in section 13.3 of the protocol. 
5.2. Non-screening criteria 
5.2.1. 
General criteria 
6. Unlikely to cooperate in the study
7. Pregnant and lactating women
8. Participation in another interventional study at the same time; participation in non-
interventional registries or epidemiological studies is allowed
9. Participant already enrolled in the study (informed consent signed)
5.2.2. 
Medical and therapeutic criteria 
10. Prior treatment with chemotherapy or radiotherapy (except steroids and intrathecal
therapy)
11. Prior surgery or bone marrow transplant related to the studied disease
12. Down Syndrome
13. Psychiatric illness/social situation that would limit compliance with study
requirements
14. Known carriers of HIV antibodies
15. History of previous or concurrent malignancy
16. History of sensitivity to polyethylene glycol (PEG) or PEG-based drugs
17. Pre-existing known coagulopathy (e.g. haemophilia and known protein S deficiency)
18. Known history of pancreatitis
19. Known history of significant liver disease
20. Significant laboratory abnormality likely to jeopardize the patients’ safety or to
interfere with the conduct of the study, in the investigator’s opinion
21. Severe or uncontrolled active acute or chronic infection
22. Uncontrolled intercurrent illness including life-threatening acute tumor lysis syndrome
(e.g. with renal failure), symptomatic congestive heart failure, cardiac arrhythmia
5.3. Inclusion criteria 
Screening criteria must still be fulfilled at the time of the inclusion visit 


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5.4. Non-inclusion criteria 
Non-screening criteria must still be fulfilled at the time of the inclusion visit 
5.4.1. 
General criteria 
23. Women of childbearing potential tested positive in a serum pregnancy test within 7
days prior to the treatment period
5.4.2. 
Medical and therapeutic criteria 
24. Inadequate hepatic function (total bilirubin > 1.5 times upper limit of normal (ULN),
transaminases > 5 x ULN)
25. Inadequate renal function defined as serum creatinine > 1.5 x ULN
5.5. Definition of women of childbearing potential and contraception methods 
Women of childbearing Potential 
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
Contraception methods 
Definition of highly effective contraception methods for the study: 
Highly effective methods of birth control refer to those which result in a low failure rate (i.e. 
less than 1% per year), when used consistently and correctly, such as combined hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception when associated with inhibition of ovulation (oral, 
injectable, implantable), some intra uterine devices (IUDs), intrauterine hormone-releasing 
system (IUS), true sexual abstinence (when this is in line with the preferred and usual lifestyle 
of the participant), bilateral tubal occlusion, male sterilization (vasectomy).  
5.6. Retest management during screening period 
A patient who has a laboratory result(s) that does not satisfy the entrance criteria may have 
the test (s) repeated once providing that the investigator judges it relevant according to the 
patient / participant previous results, or medical history and if s/he considers laboratory 
abnormalities are likely to be transient. Results of the test(s) repeated should be obtained 
within the allowed screening period. In this case the patient/participant will not be required to 
sign another informed consent, and the original patient / participant ID number assigned by 
the investigator will be used. 
In any case, the last result available for each parameter must be considered for the 
patient/participant inclusion. 
5.7. Additional information recorded at the inclusion visit 
Not applicable 


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5.8. Participant withdrawal 
5.8.1. 
Withdrawal criteria 
Information to be collected during the last visit of these participants is given in section 5.8.2. 
These follow-up modalities are used to ensure safety evaluation of all participants who 
received the IMP. 
The reasons for premature discontinuation of the study are: 
­ Adverse events according to the judgement of the investigator, including no recovery of 
safety parameters, serious hypersensitivity or adverse events delaying the IMP 
administration by more than 14 days (see section 6.1.1) 
­ Pregnancy 
­ Major deviation to protocol if it interferes with the study evaluations and/or if it 
jeopardises participant’s safety 
­ Non-medical reason (e.g. consent withdrawal, participant’s removal) 
­ Other, physician decision 
5.8.2. 
Procedure 
Upon discontinuation of treatment the investigator must: 
­ Notify the Clinical Research Associate (CRA) immediately 
­ Indicate the main reason, if there are several reasons 
­ Record this information in the eCRF 
In the case of premature withdrawal from the study due to an adverse event (event requiring 
immediate notification or not), the investigator must make every effort to collect the 
information relating to the outcome of the event. If necessary, the information will be 
collected afterwards (see section 8.9). This information is recorded in that part of the 
electronic case report form which concerns adverse events. If the investigator cannot collect 
the information from a visit, he must collect it from the doctor ensuring the follow-up of the 
participant. 
If the study is stopped as a result of an event requiring immediate notification, the procedure 
described in section 8.9.2.5 is to be implemented. 
After discontinuation of the study, the participants’ treatment is left to the physician’s 
discretion, according to local regulation and practice. Provided that the inclusion/non-
inclusion criteria are fulfilled, the participant will be proposed to enter a roll-over study (CL2-
95014-003) using lyophilized S95014 during the consolidation phase, in compliance with 
ALL-MB 2015 protocol. 
5.8.3. 
Lost to follow-up 
Not applicable 
6.
TREATMENT OF PARTICIPANTS
6.1. IMPs and NIMPs administered 
6.1.1. 
IMPs 
S95014 liquid (reference drug) and S95014 lyophilizate (test drug) are both IMPs. 


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Either lyophilized S95014 (arm 1) or liquid S95014 (arm 2) will be administered IV at the 
dose of 2500 U/m² at Day 3 of the induction phase, over 1-hour infusion. Please refer to latest 
version of the Investigator Brochure for further details. 
S95014 dosage is calculated according to body surface area (BSA). The BSA will be 
calculated by the IRS based on the height and weight measured on the day of S95014 infusion 
(all BSA calculations are rounded to 2 decimal places). Height and weight measured within 4 
days before the date of S95014 infusion will be acceptable. 
BSA (m²) = √ (Height [cm] x Weight [kg]/3600) 
Study sites are required to use only calibrated and certified scales throughout the study. 
If, for any reason, a patient included in the study is not able to receive S95014 at the 
prescribed dose of 2500 U/m² at the planned day, the infusion can be delayed. The day of 
S95014 administration will be regarded as Day 3 and the other treatments (backbone regimen 
used in the frame of ALL-MB 2015) will be postponed consequently. No dose reduction will 
be authorized during the induction phase. Beyond 14 days, if the patient cannot receive the 
IMP, he/she must be discontinued from the study. 
6.1.2. 
NIMPs 
Backbone therapy drugs administered as per ALL MB 2015 protocol (see Appendix 1) will be 
regarded as NIMPs and will not be provided by the Sponsor.  
NIMPs used during the induction phase are, as follows: 
­ Dexamethasone  
­ Methylprednisolone 
­ Vincristine 
­ Daunorubicin 
­ Idarubicin 
­ Methotrexate/cytarabine/prednisolone intrathecal 
For further details about NIMPs, please refer to respective SmPC. 
6.2. IMP dispensing 
The treatment group will be allocated via IRS using a central randomization (1:1) to either 
lyophilized S95014 (arm 1) or liquid S95014 (arm 2) of the induction phase (see Pharmacy 
manual for further details).  
IMPs will be dispensed by the pharmacist/responsible of the healthcare establishment upon 
prescription of the investigator only. 
The investigator may only use the IMPs provided for the patients involved in the study and 
treated under his/her responsibility or that of a designated co-investigator. 
For each patient, the IMPs will only be dispensed during the study. 
Further instructions for the preparation and dispensation of S95014 are described in the 
Pharmacy Manual. 


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The detachable portion of the label on the IMP box must be stuck by the investigator on an 
IMP label collection form or on the prescription form where the IMPs are dispensed by a 
pharmacist. 
6.3. Previous and concomitant treatments 
If a patient receives any drug other than S95014 and backbone therapies used in the frame of 
ALL-MB 2015 during the period from the day of informed consent to the withdrawal/end-of-
study visit, the following information will be entered in eCRF: 
-
Name of drug or therapy
-
Start date and end date of treatment
-
Route of administration
-
Indication
The following treatments are to be used with caution during the treatment period: 
­ Live vaccines 
­ Coumarin/warfarin and heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-
inflammatory medicines (e.g. ibuprofen, naproxen). 
­ Prednisone, methotrexate, vincristine, cytarabine (see ALL-MB 2015 protocol for further 
details) 
For further information about the drug-drug interactions, please refer to the latest version of 
the Investigator Brochure. 
The patient and his/her parent(s)/legal representative must be told to notify the investigational 
site about any new medications he/she takes after having signed the ICF of the study. All 
medications (other than study drugs) and significant non-drug therapies (including blood 
transfusion) administered during the study must be listed on the eCRF. 
6.4. IMP compliance 
The number of injectable vials dispensed are to be counted by the investigator or a designated 
person from his/her team and recorded in the electronic case report form and therapeutic unit 
tracking form, or an equivalent document. 
The compliance will be assessed from the method described above. 
6.5. Discontinuation of the IMP 
Not applicable 
7.
ASSESSMENT OF PHARMACOKINETICS
7.1. Methods and measurement times 
Pharmacokinetics measurements performed during the study are indicated in Table (4.1.2) 1. 
The sampling conditions, labelling, handling and storing details will be described in a specific 
technical document. 


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Sampling methods & timepoints: 
Eleven (11) sodium heparinised plasma for pharmacokinetic (serial PK samples) will be 
obtained; as follows: pre-dose, just after the end of infusion (on Day 3), 4 hours after the end 
of infusion (on Day 3), 24 hours after the end of infusion (on Day 4), 48 hours after the end of 
infusion (on Day 5), 120 hours (i.e. 5 days) after the end of infusion (on Day 8), 168 hours 
(i.e. 7 days) after the end of infusion (on Day 10), 216 hours (i.e. 9 days) after the end of 
infusion (on Day 12), 336 hours (i.e. 14 days) after the end of infusion (on Day 17), 432 hours 
(i.e. 18 days) after the end of infusion (on Day 21) and 600 hours (i.e. 25 days) after the end 
of infusion (on Day 28). 
In all participants, 2.5 mL of blood will be taken at each timepoint for pharmacokinetic 
assessment, leading to a total volume of 27.5 mL (11 timepoints overall). 
All samples should be obtained as closely as possible to the nominated time and at least 
within the following windows: 
­ Pre-dose: within 15 minutes before IMP administration (start of infusion), 
­ End of infusion and 4-hour time point: + 10 min after the end of the infusion and ± 10 min 
for 4-hour timepoint 
­ 24-hour and 48-hour post-dose samples: ± 1 hour of the nominated time
­ 5- 7- and 9-days post-dose (i.e. Day 8, Day 10 and Day 12) samples: ± 3 hours of the
nominated time
­ 14-, 18- and 25-days post-dose (i.e. Day 17, Day 21 and Day 28) samples: ±6 hours of the 
nominated time 
The accurate sampling times must be recorded in the e-CRF. 
Blood samples for end of infusion and 4-hour timepoints should be collected from the arm 
opposite from the IMP infusion, or from another site. 
All samples will be destroyed after mandatory assessment is completed and at the latest 
before the final version of the clinical report. 
Participant who meet any of the following criteria will not be evaluable for PK analysis and 
therefore will be replaced: 
­ infusion interrupted for any reason 
­ deviation in the theoretical administered dose > 10% 
­ at least one missing PK sample during the 48 first hours 
­ at least two missing PK samples after the 48-hour time point, 
PAA will be determined using a coupled enzymatic activity assay, validated according to 
current regulatory guidelines. 
The following parameters (including but not limited) will be calculated using a non-
compartmental analysis (NCA) approach based on observed plasma asparaginase activity 
(PAA) time profiles:  Area Under the Concentration-Time curve (AUC); maximum observed 
plasma asparaginase activity (Cmax); lowest observed plasma asparaginase activity (Ctrough, day
14) 14 days post-dose, time to reach the maximum PAA (Tmax), terminal half-life (T1/2). The
above PK parameters will be calculated for each patient and the corresponding descriptive


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statistics of PK parameters will be tabulated. (Arithmetic mean, SD, geometric mean, 
geometric CoV, median, min, max). 
For further details about the PK analysis, please refer to the corresponding Data Analysis Plan 
(DAP). 
8. ASSESSMENT OF SAFETY
All adverse events and other situations relevant to the safety of the participants must be 
followed up and fully and precisely documented in order to ensure that the sponsor has the 
necessary information to continuously assess the benefit-risk balance of the clinical trial. 
8.1. Specification of safety parameters 
Safety measurements performed during the study are indicated in Table (4.1.2) 1. 
Safety assessment of lyophilized vs liquid S95014 will include: 
­ adverse events (AEs) assessments 
­ physical examinations, performance status ECOG (see Appendix 3) 
­ laboratory assessments: haematology, blood biochemistry, coagulation parameters, 
urinalysis, hepatitis serology  
­ ECG measurements (triplicate) 
­ vital signs measurements 
Adverse events will be collected regardless of grade or IMP relationship and will be graded 
according to current NCI CTCAE criteria 5.0 
Any significant abnormality detected during safety assessments from the patient ICF signature 
until the withdrawal/end-of-study visit must be reported on the adequate eCRF page by the 
investigator at each visit (AE, medical history or sign & symptoms). 
8.2. Methods and measurement times 
Relevant medical history will be reported to identify any medical condition which could 
preclude patient’s inclusion: 
­ Initial diagnosis 
­ Previous chemotherapies, bone marrow transplants, surgeries, radiotherapies related to the 
studied disease 
­ Concomitant signs and symptoms related to the studied disease 
­ Concomitant and previous treatments 
Clinical examination and vital signs measurements 
­ Serum pregnancy test will only be performed for WOCBP (see Section 5.5) 
­ Complete clinical examination, height and weight measurement and ECOG PS assessment 
will be performed 
­ Vital signs measurements include blood pressure (BP), heart rate (HR) and temperature. 
BP and HR will be measured by an automatic device in supine position after 5 min rest. 


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Vital signs and performance status measurements will be performed during screening, before 
and after S95014 infusion (Day 3, pre-dose and post-dose) and during the withdrawal/end-of-
study visit. 
Laboratory tests 
All laboratory tests performed during the study period will be assayed in an identified 
laboratory at hospital. Inter-visits laboratory tests could be assayed by local laboratories. In all 
cases, the full validated set of normal ranges values will be collected, as well as any update in 
these values during the study and must be documented in the corresponding eCRF pages. 
All samples will be destroyed after mandatory assessment is completed and at the latest 
before the final version of the clinical report. 
The laboratory parameters collection plan is described in Table (8.2) 1.  
Blood haematology, blood biochemistry, blood coagulation and urinary analysis will be 
performed during screening, before S95014 infusion (Day 3, pre-dose), at Day 10, Day 17, 
Day 24 and during the withdrawal/end-of-study visit. 
Other laboratory tests (i.e. hepatitis serology and pregnancy test) will be performed during 
screening and during the withdrawal/end-of-study visit. 
Table (8.2) 1 - Local Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Haematology 
Haematocrit, Haemoglobin, Red blood cells (RBC), White blood cells (WBC), Platelets, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Blasts in 
absolute value and in %) 
Biochemistry 
Albumin, Alkaline Phosphatase (ALP), ALT, AST, Ammonia, Bicarbonates, Gamma-
glutamyl-transferase (GGT), Lactate dehydrogenase (LDH), Calcium, Phosphorus, 
Sodium, Potassium, Creatinine, Total Bilirubin, Total Cholesterol, LDL, HDL, 
Triglycerides, BUN or Urea, Uric Acid 
Amylase, Lipase, Glucose  
Urinary analysis 
Macroscopic Panel (Dipstick) (Blood, Glucose, Ketones, Protein) 
If the dipstick test is at least 2+ on one or more parameter(s), quantitative urinary 
biochemistry tests will be performed on the abnormal parameter(s) 
Blood coagulation 
Prothrombin time - International Normalized Ratio (INR), fibrinogen, protein S activity, 
antithrombin activity, activated Partial Thromboplastin Time (aPTT), D-dimer, FDP  
Hepatitis serology 
HbsAg, HbsAb, HbcAb, if HbsAg or HbcAb positive check viral load (HBV-DNA) at 
baseline, HCV RNA-PCR, HEV RNA-PCR 
Pregnancy Test 
Pregnancy testing is mandatory at inclusion (serum) and at withdrawal/end-of-study visit 
(serum) for WOCBP 
All samplings for biochemistry should be taken in fasting conditions. 
Abnormal laboratory values or test/exams results (i.e. ECG recording) will constitute an AE if 
they are: 


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­ associated with signs and symptoms, or 
­ deemed clinically significant in the investigator’s opinion, or 
­ if they require curative therapies, or
­ associated with delay of study medication, or
­ associated with study discontinuation 
Triplicate Electrocardiograms (ECG) will be assessed during screening and the 
withdrawal/end-of-study visit. In addition, ECG results will be collected, if made available, as 
per ALL-MB 2015 protocol timepoints (e.g. before and after anthracyclines administration) 
LVEF assessment will be performed through echocardiography or MUGA scan during 
screening and during the withdrawal/end-of-study visit 
8.3. Definition of Adverse events 
An adverse event is defined as any untoward medical occurrence in a subject participating in a 
clinical study, whether or not there is a causal relationship with the IMP and/or experimental 
procedures, occurring or detected from the date the participant signs the information and 
consent form, irrespective of the period of the study (periods without administration of the 
IMP (e.g. screening period) are also concerned). 
An adverse event can therefore be: 
­ any unfavourable and unintended sign (including an abnormal finding from an additional 
examination such as lab tests, X-rays, ECG, …) which is deemed clinically relevant by the 
investigator,  
­ any symptom or disease, 
­ any worsening during the study of a symptom or a disease already present when the 
participant entered the study (increase in frequency and/or intensity), including the studied 
pathology, 
and detected during a study visit or at an additional examination or occurred since the 
previous study visit (including relevant event reported in participant’s diary or safety 
evaluation scale). 
Of note: 
­ Any hospitalisation for administration of anti-tumoral treatment and/or associated 
protocol (during or after the study) or other care measures for cancer (e.g. overnight 
hospital stay to receive a blood or platelets transfusion), for social reasons, 
educational purpose (e.g. learning of diabetes management by the participant) or routine 
check-up should not be considered as an adverse event and should not be reported in the e-
CRF. The following procedures, whether planned before the study or not, whether leading 
to a hospitalisation or not, should not be reported in the e-CRF and kept in the source 
data (or patient file):  
o therapeutic procedures related to a non-aggravated medical history (e.g. cataract
extraction not due to an aggravation of the cataract during the study, haemodialysis
sessions related to a renal insufficiency not aggravated during the study),
o prophylactic procedures (e.g. sterilisation, wisdom teeth removal),
o comfort procedures (e.g. cosmetic surgery),
o control procedures of a pre-existing condition without aggravation (e.g. colonoscopy to
control the remission of colon cancer).


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8.4. Definition of Serious adverse events 
Any adverse event that at, any dose: 
­ results in death, 
­ is life-threatening(1), 
­ requires inpatient hospitalization or prolongation of existing hospitalization, 
­ is medically significant(2), 
­ results in persistent or significant disability/incapacity(3), 
­ is a congenital anomaly/birth defect(4). 
(1) Life-threatening in this context refers to an event in which the participant was at risk of death at the
time of the event; it does not refer to an event which hypothetically might have caused death if it were
more severe.
(2) Any event that might not be immediately life-threatening or result in death or hospitalisation, but
might jeopardise the participant or might require intervention to prevent one of these outcomes (for
example: oedema or allergic bronchospasm that required intensive treatment at home, blood dyscrasia,
convulsions that do not result in hospitalisation, or development of drug dependence or drug abuse).
The investigator should exercise his/her scientific and medical judgement to decide whether or not
such an event requires expedited reporting to sponsor.
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the
participant to lead a normal life, in other words leads to a persistent or permanent significant change,
deterioration, injury or perturbation of the participant's body functions or structure, physical activity
and/or quality of life.
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or
women) or during pregnancy that resulted in an adverse outcome in the child.
8.5. Definition of Overdose 
This refers to any intake of a quantity of IMP or a product other than the IMP taken as part of 
the protocol (NIMP) which is above the maximum dose recommended in the study protocol, 
independently of the occurrence of any adverse event. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol or in ALL-MB 2015 protocol for NIMP.  
8.6. Definition of Adverse event of special interest 
An adverse event of special interest (AEOSI) is one of scientific and medical interest or 
concern regarding the IMP for which recording rules, special documentation such as hospital 
records and/or adjudication committee could be appropriate. It may be a serious or non-
serious AE that may require further investigation in order to be characterized and understood.  
AEOSI include: 
­ Grade ≥ 3 ALT/AST increase or grade ≥ 3 hyperbilirubinemia 
­ Grade ≥ 3 haemorrhage or grade ≥ 3 thromboembolic events  
­ Grade ≥ 3 pancreatitis 
­ Grade ≥ 3 hypersensitivity 


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Those adverse events have been identified in the Risk Management Plan (RMP) as important 
identified risks with S95014. A close monitoring and a specific documentation will be 
required, as described in sections below. 
8.6.1. 
Hepatotoxicity monitoring 
Considering the safety profile of the compound, an increase in serum liver enzymes should be 
followed by repeat testing including all the usual serum measures (at least ALT, AST, ALP, 
and total bilirubin) to confirm the abnormalities and to determine if they are increasing or 
decreasing as follows: 
-
For isolated total bilirubin increase Grade 3 (> 3.0 x ULN) or isolated AST or ALT
increase Grade 3 (> 5.0 x ULN), the patient should be monitored weekly including Liver
Function Tests [LFTs: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin >
2.0 x ULN), alkaline phosphatase (fractionated if alkaline phosphatase > 2.0 x ULN) and
gamma-glutamyl transpeptidase], or more frequently if clinically indicated, until values
have resolved to baseline or stabilized over 4 weeks
-
For AST or ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN, repeat liver
function tests as soon as possible, preferably within 48 hours from awareness of the
abnormal results, then with weekly monitoring of LFTs, or more frequently if clinically
indicated, until AST, ALT, or bilirubin have resolved to baseline or stabilized over
4 weeks
Clinically significant abnormalities have to be carefully documented in the patient’s medical 
file.  
Additional tests to evaluate liver function such as INR (or biopsy if appropriate) may be 
performed as appropriate. Close observation and documentation also include: 
-
Obtaining a more detailed history of symptoms and prior or concurrent diseases, obtaining
a history of concomitant drug use (including non-prescription and herbal and dietary
supplement preparations), alcohol use
-
Performing liver imaging (ultrasound, magnetic resonance or computerized tomography) to
evaluate biliary tract or liver disease
-
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis;
hypoxic/ischemic hepatopathy; NASH; and biliary tract disease
-
Considering gastroenterology or hepatologist consultations
A specific form (see Appendix 4) will be completed. 
8.6.2. 
Pancreatitis monitoring 
Serum amylase and/or lipase levels should be monitored frequently to identify early signs of 
pancreatic inflammation. A Computerized Tomography (CT) scan or other imaging test to 
assess the pancreas, liver, and gallbladder could be performed within 1 week of the first 
occurrence of any ≥ Grade 3 amylase and/or lipase increase, or as clinically indicated.  
As impaired glucose tolerance may occur with concomitant use of S95014 with prednisone, 
blood glucose levels should be monitored.  
8.6.3. 
Coagulopathy monitoring 
Increased prothrombin time (PT), increased activated partial thromboplastin time (aPTT), and 
hypofibrinogenaemia can occur in patients receiving pegaspargase. Coagulation parameters 
should be monitored at baseline and periodically during and after treatment, particularly when 


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other medicinal products with procoagulant or anticoagulant effects are used simultaneously, 
such as acetylsalicylic acid and non-steroidal anti-inflammatory medicinal products, or when 
concomitant chemotherapy regimen including methotrexate, daunorubicin, corticosteroids is 
administered. 
In case of haemorrhage grade ≤ 2, evaluate for coagulopathy and consider clotting factor 
replacement as needed.  
8.6.4. 
Hypersensitivity monitoring 
Prophylactic treatment with acetaminophen, histamine-1 blocker, and corticosteroid will be 
administered to prevent hypersensitivity.  
Patients’ vital signs (BP, HR, temperature) should be monitored during S95014 infusion and 
for 1 hour after the end of S95014 infusion. Resuscitation equipment and other appropriate 
means for the treatment of anaphylaxis should be available (epinephrine, oxygen, intravenous 
steroids, etc.).  
S95014 infusion should be interrupted in patients with serious hypersensitivity reactions and 
patients should be discontinued from the study (see section  5.8.1). 
8.7. Definition of Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. without delay and within 24 hours at the latest) 
to the sponsor if it is: 
­ a serious adverse event, 
­ an adverse event of special interest, (if applicable, as defined in § 8.6, otherwise delete) 
­ an overdose of the IMP/NIMP even if asymptomatic,  
­ any intake of the IMP/NIMP by a person around the participant, 
­ a pregnancy. 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) 
It is important that the investigator gives his/her own opinion regarding the seriousness, the 
severity of the event as well as the cause-effect relationship between an adverse event and 
the research (IMP or study protocol). This evaluation must be assessed by the investigator and 
reported in the AE form. In addition, the sponsor will be responsible for the evaluation of the 
expectedness of the event (See Section 8.9.3). 
The Seriousness should be evaluated according to international guidances (see definition 
Section 8.4, in accordance with ICH Topic E2A and DIRECTIVE 2001/20/EC OF THE 
EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April). 
The severity of all AEs will be graded according to the National Cancer Institute Common 
Toxicity Criteria for Adverse Event (NCI-CTCAE) on a five-point scale (Grade 1 to 5): 
­ Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 


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­ Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL1. 
­ Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL2. 
­ Grade 4: Life-threatening consequences; urgent intervention indicated. 
­ Grade 5: Death related to AE. 
The cause-effect relationship 
The investigator has to assess in the AE form if the AE is related or not to the research, 
meaning:  
­ adverse event related to IMP(s) 
­ adverse event related to study protocol i.e. related to:  
o
a procedure scheduled in the study protocol (i.e. exercise test, MRI, etc.), or
o
a change or withdrawal of previous / concomitant treatment related to the conditions of
the protocol or
o
a product other than the IMP, taken as part of the protocol (NIMP or other);
Moreover, the investigator has to assess if the AE is related to disease progression. Cases 
ticked “related” by the investigator or judged by the sponsor as having a reasonable suspected 
causal relationship to the IMP (AE linked to the mechanism of action of the IMP…), will be 
considered as suspected Adverse Drug Reaction. In general, if a relationship between AE and 
IMP is at least reasonably possible (i.e. the relationship cannot be ruled out) it is to be 
considered as “related”. 
8.9. Reporting procedures 
8.9.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see sections 8.3 to 8.7) must be reported 
to the sponsor on an adverse event form if it occurred: 
­ before the first intake of the IMP for events related to the research 
­ at any time after the administration of IMP, up to the participant’s last study visit for all 
events, 
­ up to 30 calendar days after the IMP administration for all ERIN, regardless of the 
supposed role of the research,  
­ irrespective of the time of onset in case of serious adverse event related to the research. 
Of note, events occurring between the signature of the informed consent and the first 
administration of the IMP for which the investigator does not consider an association with any 
procedure/condition required by the study protocol must be reported as medical history or as 
signs and symptoms related to the studied disease in the dedicated form of the CRF.  
1 Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden”. 


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8.9.2. 
Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
­ Note in the participant's medical file the date on which he/she learned of the event (at a 
follow-up visit or a telephone contact with the participant or a third person, …) and any 
other relevant information which he/she has learned of the event, 
­ Assess the event in terms of seriousness, intensity and causality, 
­ Report the event to the sponsor using the AE form (in case of ERIN, the reporting should 
be done immediately), 
­ Document the event with additional useful information,  
­ Ensure the follow-up of the event,  
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IEC, in 
accordance with local regulations. 
Moreover, the investigator must report to the sponsor and/or to the IEC and/or to the 
Competent Authorities in accordance with the local regulation, any new information that 
might materially influence the benefit-risk assessment of the IMP or that would be 
sufficient to consider changes in the IMP administration or in the overall conduct of the 
clinical investigation. 
8.9.2.1. 
Documentation of the event 
The investigator must ensure that all events are well documented. In particular for ERIN, 
he/she should provide the sponsor, as they become available, with anonymized copies of the 
documents which provide additional useful information, such as hospital admission reports, 
reports of further consultations, laboratory test reports, reports of other examinations aiding 
diagnosis (where possible, the results from pre-IMP assessments should be appended for 
comparison with the results obtained under IMP), or the autopsy report, if autopsy is 
performed. 
8.9.2.2. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the participant is appropriate to the nature of 
the event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, intensity, seriousness, measures taken, causality or 
outcome regarding an adverse event already reported must be written up in a new complete 
evaluation of the event documented on an “Adverse event” page previously created for the 
event. 
If the adverse event has not resolved at the participant's final visit in the study, the participant 
must be followed up suitably and any information on the outcome of the event will be noted 
on an « Adverse Event » page previously created for the event 
If the follow-up of the participant is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the participant's general practitioner, …), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the participant. 


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8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP/NIMP a person 
around the participant) 
Pregnancy 
If a female participant in the study becomes pregnant, the investigator must: 
­ stop immediately the IMP (if the pregnancy is a non-screening/exclusion criterion), 
­ report it on an « Adverse Event » page as well as on the specific paper pregnancy form (1st 
page) to be notified immediately (ERIN), 
­ contribute to the follow-up of this pregnancy and provide the sponsor with information 
concerning this follow-up (notably using the 2nd page of the specific paper pregnancy 
form). 
­ If the partner of a participant becomes pregnant during the course of the study, the 
pregnancy should not be reported in the e-CRF. The investigator should immediately 
contact the sponsor (contact details provided in the investigator’s study file) who will 
inform him/her about the procedure to be followed. 
Overdose of IMP or NIMP 
­ In case of overdose, the investigator should report it on an “Adverse Event” page to be 
notified immediately (ERIN).  
­ Overdose should be followed-up to ensure that the information is as complete as possible 
with regards to: 
o dose details (number of units, duration…) and, if multiple overdose, details regarding
other medicinal products or substance,
o context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental (error
in prescription, administration, dispensing, dosage),
o related signs and symptoms (“No related adverse events” to be reported otherwise),
o outcome.
­ Insofar as possible, a blood sample should be collected for assay of the IMP taken.  
Intake of IMP/NIMP by a person around the participant 
This event should not be reported in the e-CRF. The investigator should immediately contact 
the sponsor (contact details provided in the investigator’s study file) who will inform him/her 
about the procedure to be followed. 
8.9.2.4. 
Recording Methods in the e-CRF  
Adverse events must be documented on the « Adverse Event » page of the e-CRF. 
In case of chronic disease: 
­ if the disease is known when the participant enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks) will be documented as an adverse event,  
­ if the disease is detected during the study and if repeated episodes enable diagnosis of a 
chronic disease, the episodes will be grouped on the «Adverse Event» page previously 
created for the event which will clearly describe the diagnosis. 


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8.9.2.5. 
Procedure for an event requiring an immediate notification 
In case of an event requiring an immediate notification, the investigator must: 
­ Immediately after being informed of this event, fill in the participant's medical file as 
well as the « Adverse Event » page of the e-CRF according to the general instructions 
available in the e-CRF, without waiting for the results of the clinical outcome or of 
additional investigations. When data will be submitted into Inform, an e-mail will be 
immediately and automatically sent to the sponsor. 
­ Provide the sponsor (person designated in the contact details provided in the investigator’s 
study file), as they become available, with anonymized copies of the documents which 
provide additional useful information, 
­ Fulfil his/her regulatory obligations to the Competent Authorities and/or to the IEC, in 
accordance with local regulations. 
If an adverse event initially non-serious worsens and becomes serious (ERIN), this must be 
reported immediately on an "Adverse event" page of the e-CRF. 
In case the e-CRF is unavailable when the investigator was informed of the ERIN, he/she 
should: 
­ Immediately fill in a paper "Adverse event" page: 
o For serious event on a paper "Adverse event – Initial information" page,
o For event initially non-serious on a paper "Adverse event – Initial information" page,
and the worsening leading to seriousness on a paper "Adverse event – Additional
information" page,
­ Immediately send them by fax or by e-mail to the person(s) designated in the contact 
details provided in the investigator’s study file or outside working hours, the 24-hour 
phone line (international prefix followed by 33.1.55.72.60.00 for a call from outside 
France, and/or the 24-hour phone line of the ICTR in Russia 8 495 9370700, ext. 2),  
­ As soon as the e-CRF becomes available, the investigator should enter these data in the « 
Adverse Event » page of the e-CRF. 
8.9.3. 
Responsibilities of the sponsor 
In accordance with international guidances, the assessment of the seriousness and the 
causality of adverse events are usually made by the investigator but falls also under sponsor’s 
duties, who is responsible for ensuring that all suspected unexpected serious adverse reactions 
are reported to Competent Authorities and Ethics Committees.  
The sponsor will review the seriousness of the adverse events and the causality of (at least) 
the serious adverse events, whether reported by the investigator or upgraded by the sponsor. 
The causality and the seriousness may be upgraded (but never downgraded). Anonymized 
copies of documents providing useful information such as reports of further consultations, 
laboratory tests reports, reports of other examination aiding diagnosis may be asked for the 
event assessment. If the assessments of the investigator and the sponsor are different, both 
will be reported in the clinical study report. 
In addition, the sponsor is responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the IMP. 


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Independently of the regulatory obligations of the investigator, and according to the 
requirements stated in ICH Good Clinical Practice guidelines and local regulations, the 
sponsor must report the pharmacovigilance data and any new safety finding likely to affect 
the benefit /risk balance of the product to the appropriate Authorities and to all the 
investigators involved. Any new safety finding likely to affect the benefit /risk balance of the 
product will be also notified to the trial subjects involved - through the investigators - as 
mentioned in 13.4 "Modification of the information and consent form" 
9.
OTHER 
ASSESSMENTS 
NOT 
SPECIFICALLY 
RELATED 
TO
PHARMACOKINETICS OR SAFETY
9.1. Assessments related to screening/inclusion criteria 
See section 4.1.2. 
9.2. Assessment of plasma asparaginase activity 
As a secondary endpoint, the achievement of plasma asparaginase activity (PAA) ≥ 0.1 U/mL 
will be assessed 7, 14, 18 and 25 days after the S95014 infusion (i.e. Day 10, Day 17, Day 21 
and Day 28). Samples collected for PAA assessment will be the same as for PK analysis to 
avoid duplicating sample collection. 
PAA will be determined using a coupled enzymatic activity assay, validated according to 
current regulatory guidelines. 
All samples will be destroyed after mandatory assessment is completed and at the latest 
before the final version of the clinical report. 
The sampling conditions, labelling, handling and storing details will be described in a specific 
technical document. 
9.3. Assessment of immunogenicity  
The occurrence of neutralizing antibodies and associated asparaginase inactivity can be 
related to a potential silent inactivation, which is characterized by the formation of 
neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident 
allergic reaction (Van der Sluis, 2016).  
Immunogenicity assessment will include the detection of binding antibodies against S95014 
as well as antibodies against PEG in samples taken during the treatment period, at pre-dose, 
14 days and 25 days post dose (i.e. Day 17 and Day 28). The test item is the presence or 
absence of the production of anti-drug antibodies (ADA). 
This evaluation will be based on qualitative enzyme-linked immunosorbent assays (ELISA) 
using S95014 as coating antigen. All positive samples will be further confirmed by 
competitive ELISA for the presence of binding anti S95014 antibodies. Samples, when 
confirmed positive, will then be assayed for anti-PEG antibodies. For all these assays, 
antibody status (positive or negative) will be reported. 
The antibody positive samples will be further diluted and tested, and the highest sample 
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In the absence of a validated neutralizing antibody assay, the neutralizing potential of anti-
drug antibodies in positive samples will be evaluated based on the concomitant results of the 
serum asparaginase activity. 
All assays are validated with respect to cut-point, precision, linearity, short-term stability, 
freeze-thaw stability and drug interference. 
Patients positive for ADA should be monitored every 3 months in the roll-over study protocol. 
All samples will be destroyed after mandatory assessment is completed and at the latest 
before the final version of the clinical report. 
The sampling conditions, labelling, handling and storing details will be described in a specific 
technical document. 
9.4. Assessment of biomarkers 
Not applicable 
10. STATISTICS
The analysis methods for PK, PAA, immunogenicity and safety endpoints are specified 
below. Unless otherwise specified, categorical data will be summarized using frequencies and 
percentages, and continuous data will be summarized using descriptive statistics. The 
descriptive statistics will be the number of subjects, mean, standard deviation, minimum, 
median, and maximum.   
10.1. Population 
10.1.1. Determination of sample size 
This study is a two-arm parallel 1:1 randomized trial to evaluate the PK comparability 
between liquid and lyophilized S95014 formulations. For both AUC and Cmax, the coefficient 
of variation (CoV) of 0.30 is assumed based on the estimation of CoV for liquid S95014 from 
a previous study (Angiolillo, 2014). It is also reasonable to assume a geometric mean ratio 
(GMR) of 100% for Cmax and AUC, since no impact of an absorption phase is expected 
because both formulations are delivered intravenously. In addition, the CMC investigations 
have shown that once the lyophilised formulation is reconstituted, the characteristics of the 
solution are comparable to the ones of the liquid formulation. Assuming a CoV of 0.30 and a 
true geometric mean ratio (GMR) of 100%, a total of 78 evaluable subjects (39 subjects per 
arm) will provide approximately 90% power to establish the PK comparability. Assuming that 
10% of the included patients will not be evaluable (e.g. missing PK timepoint etc.), 88 
subjects are expected to be included to allow 78 evaluable patients.  
10.1.2. Analysis subset 
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who have been randomized in the study. 
Subjects will be classified according to their assigned treatment arm. 
Safety Analysis Set 


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The safety analysis set (SAS) is defined as the set of all subjects who have received at least 
one dose of S95014 in the study. Subjects will be classified according to treatment received. 
The safety endpoints will be analysed in the safety analysis set. 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) will include all subjects who have received at least 
one dose of IMP and are evaluable for PK analysis. The PK dataset will include only the 
subjects who had enough samples collected to provide interpretable PK results with no 
deviations that might have affected the PK interpretation (e.g. infusion interrupted for any 
reason, deviation in the theoretical administered dose > 10%, at least one missing PK sample 
during the 48 first hours, ≥ 2 PK samples after the 48-hour time point). The ADA-positive 
patients will be a priori included in the PKAS since no impact was identified based on the 
population PK model. Nevertheless, if any evidence of such an impact can be identified in the 
study, a second PKAS will be defined that will include the patients for whom none of the 
ADA assessment time points is positive. 
Immunogenicity Analysis Set 
The immunogenicity analysis set will include all subjects who have received at least one dose 
of IMP and have at least one post-dose sample evaluable for immunogenicity testing. 
10.2. Statistical analysis 
10.2.1. Pharmacokinetics analysis 
The pharmacokinetic analysis will be performed on the Pharmacokinetic Analysis Set 
(PKAS). The PKAS is defined as all included participants having completed the treatment 
period without deviation affecting pharmacokinetic interpretation (see section 10.1.2).  
Final analysis will be performed after the database freezing and the electronic transfer of 
PAA. The dataset needed for final analysis will be prepared by extraction under the 
supervision of Central Business Intelligence (CBI) Department from the I.R.I.S database 
using SAS® PC version 9.2 software or later.  
A non-compartmental pharmacokinetic analysis will be performed on the individual plasma 
concentrations-time profiles of PAA, using the actual administration and sampling times after 
administration. Calculated PK parameters will be described according to a separate Data 
Analysis Plan (DAP) such as: Area Under the Concentration-Time curve (AUC); maximum 
observed plasma asparaginase activity (Cmax); lowest observed plasma asparaginase activity 
(Ctrough, day 14) 14 days post-dose, time to reach the maximum PAA (Tmax), terminal half-life 
(T1/2). The above PK parameters will be calculated for each patient and the corresponding 
descriptive statistics of PK parameters will be tabulated. (e.g. number of patients, arithmetic 
mean, SD, geometric mean, geometric CoV, median, min, max). 
Descriptive statistics of PAA (e.g. number of patients, arithmetic mean, geometric mean, % 
coefficient of variation [%CV], SD, minimum, median, and maximum) will be also calculated 
and tabulated per sampling time. Plasma concentrations over time will be plotted in 
semilogarithmic and linear formats as mean ± SD and as median (Q1, Q3). 
Bioequivalence tests will be used to compare pharmacokinetic parameters of asparaginase 
activity in lyophilized formulation versus liquid formulation using the PKAS. Individual 


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values of Cmax and AUC will be logarithmically transformed prior to statistical analysis. An 
additional comparison will also be performed on Ctrough, day 14 for information purpose. 
An analysis of variance (ANOVA) will be performed for the natural logarithms of PK 
parameters (AUC, Cmax and Ctrough, day 14). The ANOVA model will include fixed effect for 
formulation. The two one-sided tests procedure will be performed on the geometric mean 
ratio (GMR) between test (lyophilized pegaspargase) and reference (liquid pegaspargase) 
treatments. This will be done via a 90% confidence interval for the ratio obtained in the 
framework of the ANOVA for the logarithms. The confidence interval will be obtained by 
exponentiation of the upper and lower 90% confidence limits for the difference of logarithm 
means. PK comparability between the test treatment and the reference treatment will be 
concluded if the 90% confidence interval for AUC and Cmax GMR is within the [80.00%; 
125.00%] range.  
For further details about the PK analysis, please refer to the Data Analysis Plan (DAP). 
10.2.2. 
Safety Analysis 
All subjects included in the safety analyses will be evaluated by the actual treatment arms 
unless otherwise specified. 
10.2.2.1. 
Adverse Events 
Treatment emergent adverse events (TEAE) will be assessed according to the National Cancer 
Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE) v5.0. Laboratory 
abnormalities will be classified into Common Terminology Criteria (CTC) grade according to 
CTCAE v5.0 and will be reported as adverse events.  
Adverse events will be summarized in hierarchical tables, presenting the number and 
percentage of patients having at least one AE, and having at least one AE in each primary 
system organ class and for each preferred term using MedDRA coding. AEs will be sorted by 
descending frequency, and alphabetically where frequency is tied. Such summaries will be 
produced for all AEs, serious adverse events (SAEs), grades 3 or 4 AEs, AEs leading to study 
discontinuation, and AEs leading to dose-adjustment or interruption of any of the drugs of the 
treatment. All of these summaries will be by system organ class, preferred term, treatment 
group and, in some case, maximum grade. Most of the summaries will be produced twice, 
once for all events regardless of study treatment relationship, and once for events suspected to 
be study treatment related. All deaths will be listed and summarized.  
All adverse events will be listed, and any other information collected (e.g., start/end dates and 
duration of adverse event, severity or relatedness to study medication) will be listed as 
appropriate.  
AEOSI will be summarized separately. All such events will be identified prior to database 
lock.  
10.2.2.2. 
Other Safety Evaluations 
Descriptive statistics of laboratory parameters and continuous variables of vital signs and 
ECG will be calculated by treatment group for each time point. Shift tables for qualitative 
urinalysis results at each time point after the start of administration will be created. Height, 
weight, body surface area (BSA) and body mass index (BMI) will be summarized over visit by 
treatment group.   


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Shift tables will be provided for laboratory parameters to compare a subject’s baseline 
laboratory evaluation relative to the worst value during the treatment period using Common 
Terminology Criteria for Adverse Events (CTCAE) grades. In addition, the normal laboratory 
ranges will be used to evaluate whether a particular laboratory test value was normal, low, or 
high for each visit value relative to whether or not the baseline value was normal, low, or high 
(including category “high and low”). Subjects with abnormal laboratory values will be listed 
and values outside the normal ranges will be flagged. 
10.2.3. 
Analysis of Plasma Asparaginase Activity 
Observed individual Plasma Asparaginase Activity (PAA) level 7 days (Day 10), 14 days 
(Day 17), 18 days (Day 21) and 25 days (Day 28) after administration of either liquid or 
lyophilized S95014 will be tabulated by treatment group together with descriptive statistics 
(Arithmetic mean, SD, geometric mean, geometric CV, median, min, max).  
The number and proportion of patients achieving a PAA of ≥ 0.1 U/mL after the 
administration of either liquid or lyophilized S95014 among patients with evaluable Day 10, 
Day 17, Day 21 and Day 28 PAA data will be summarized by treatment group along with a 2-
sided 95% Clopper-Pearson confidence interval (CI).  
10.2.4. 
Population Analysis 
10.2.4.1. 
Subject Disposition 
Subject disposition will be tabulated for all subjects by summarizing the number and 
percentage of subjects who are included in each analysis set, completed study treatment, 
discontinued from the study and by the primary reason for discontinuation. 
A listing will present dates of study discontinuation and the primary reason, if applicable for 
each subject. 
10.2.4.2. Demographic and Baseline Characteristics 
Demographic and baseline measurements will be summarized for the safety analysis set using 
standard descriptive summaries or categorical summaries, as appropriate. In addition to the 
summary tables, a listing will be provided for all demographic and baseline characteristics 
data. In addition, listing of medical history will be provided. 
10.2.4.3. Concomitant Medication 
Concomitant medication for each subject will be listed. 
10.2.5. 
Immunogenicity Analysis 
The assessment of anti-drug antibodies includes binding and neutralizing antibodies to 
S95014 and binding anti-PEG antibodies.  
The number and proportion of patients having anti S95014 ± anti-PEG antibodies 14 and 25 
days (i.e. Day 17 and Day 28) after the administration of either liquid or lyophilized S95014 
during the induction phase will be summarized by treatment group.  
Results will be reported as follows: 


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­ Pre-existing anti-S95014 or anti-PEG antibodies: number and proportion of samples 
confirmed positive at baseline.  
­ Seroconversion upon treatment: number and proportion of samples converted from 
negative at baseline to positive at Day 17 and Day 28. If a confirmed positive sample at 
baseline has titer increase at Day 17 or Day 28 by more than 4-fold then it will be included 
within the seroconverters. 
On a case-by-case approach, the impact of positive anti S95014 and anti-PEG antibodies will 
be investigated: 
­ On the pharmacokinetics through the temporal association of antibodies with the loss of 
asparaginase activity (neutralizing antibodies) 
­ On the safety through the temporal relationship with treatment-emergent hypersensitivity 
and anaphylactic reactions. 
A patient starting with pre-existing antibodies (positive baseline) will not be considered for 
positive post-baseline anti-drug antibodies. A patient with missing baseline will be considered 
as negative baseline to be conservative. 
10.3. Handling of Missing, Unused, and Spurious Data 
Adverse events (AEs) 
­ Handling of unknown causality assessment: 
o
If a subject experience an AE with a missing causality assessment, the relationship of
the AE will be counted as “related”.
­ Handling of unknown severity grades: 
o
If a subject experiences more than one AE categorized under the same preferred term,
one of them is categorized as “severe” and one of them is categorized as “unknown”,
the severity of this AE should be counted as “severe”.
o
If a subject experiences more than one AE categorized under the same preferred term,
one of them is categorized as “mild” or “moderate” and one of them is categorized as
“unknown”, the severity of this AE should be counted as “unknown”. A column
“UNK” should be inserted for those AEs at the end of the table (before the “Total”
column if applicable).
Immunogenicity 
Missing baseline anti-drug antibody results will be imputed as negative. 
10.4. Planned Interim Analysis 
Not applicable 
10.5. Procedures for Reporting Changes to the Planned Analysis  
Details of planned analyses will be specified in the Statistical Analysis Plan (SAP). Changes 
to the planned analysis will be documented in SAP amendments. The SAP will be finalized 
prior to the database lock. 


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11. DIRECT ACCESS TO SOURCE DATA / DOCUMENTS
The investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IEC, and of the Competent Authorities to have direct access to source 
data / documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE
12.1. Study monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial follows the currently approved protocol/amendment(s), with GCP, 
and with applicable regulatory requirement(s).  
­ Monitoring for this study will be performed by the structure mentioned in Section 1.  
­ Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports.  
Management of the trial in the event of National or International Public Health Emergency 
such as Covid-19 pandemic is described in Appendix 5. 
12.1.1. Before the study 
The investigator will allow the monitor to visit the site and facilities where the study will take 
place in order to ensure compliance with the protocol requirements. 
Training sessions may be organised for the investigators and/or instruction manuals may be 
given to the investigators. 
12.1.2. During the study 
The investigator will allow the monitor to: 
­ review of the study site’s processes and procedures, 
­ verify appropriate clinical investigator supervision of study site staff and third-party 
vendors, 
­ inspect the site, the facilities and the material used for the study, 
­ meet all members of his/her team involved in the study, 
­ consult the documents relevant to the study, 
­ have access to the electronic case report forms (i.e. access to an analogic phone line or 
his/her computer), 
­ check that the electronic case report forms have been filled out correctly, 
­ directly access source documents for comparison of data therein with the data in the 
electronic case report forms, 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 


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The study monitoring will be carried out at regular intervals, depending on the recruitment 
rate and / or the investigation schedule, and arranged between the investigator and monitor. 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerised medical file 
If computerised medical files are used, and if the computer system allows, no change made in 
the medical files by the investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the 
prior information (i.e. audit trail). The investigator will save data at regular intervals. 
The investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the 
computer system. 
If the computerised medical files are considered as not validated by the sponsor, the 
investigator undertakes: 
­ at the start of the study, to print the medical files of all participants allowing a reliable 
verification of the study criteria (e.g. medical history/previous treatments/ characteristics of 
the studied disease documented within the period of time defined by the study protocol), 
­ during the study, to print in real time each data entry and each data change. 
The investigator will personally sign, date and give the number of pages on the first or last 
page of each print-out. At each visit by the monitor, the investigator will provide all the print-
outs of the medical files of the participants. The monitor will personally sign and date the first 
(or last) page then initial all pages in each paper print-out. 
If the computer system allows the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
participants and the records of the changes made. Each print-out will be personally dated and 
signed, by the investigator and the monitor on the first page. The number of pages will also be 
indicated by the investigator and the monitor on the first page. 
If the computerised medical files are considered as validated by the sponsor, the investigator 
undertakes to give access to the monitor to the computerised medical files of all participants. 
If the monitor cannot access to the tracking of the changes made to the medical files, the 
investigator will supply the monitor, at each visit, with a print-out of the records of the 
changes made to the medical files of the participants. Each print-out will be personally dated 
and signed, by the investigator and the monitor on the first page. The number of pages will 
also be indicated by the investigator and the monitor on the first page. 
The investigator undertakes to keep: 
­ all medical file print-outs signed and dated by him/her and by the monitor when the 
computer system is considered as not validated by the sponsor,  
­ if the computer system used allows changes to be made, the print-outs of the audit trail 
when the computer system is considered as not validated by the sponsor or when the 
monitor cannot access to the audit trail in the computer system, 
­ all original source-documents (originals of specific examinations, informed consent forms, 
therapeutic unit tracking form...). 


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12.3. Audit - Inspection 
The investigator should be informed that an audit may be carried out during or after the end of 
the study. 
The investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the sponsor and/or the study centre(s). The sponsor will inform 
the investigators concerned immediately upon notification of a pending study centres 
inspection. Likewise, the investigator will inform the sponsor of any pending inspection. 
The investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ to inspect the site, facilities and material used for the study, 
­ to meet all members of his/her team involved in the study, 
­ to have direct access to study data and source documents, 
­ to consult all the documents relevant to the study. 
If the computerised medical file is considered as not validated, the investigator undertakes to 
provide all the source-documents and the print-outs of the medical files of the participants 
and, if the computer system used allows, the record of the changes made during the study. 
If the computerised medical file is considered as validated, the investigator undertakes to: 
­ give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerised medical files of all participants, 
­ provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 
13. ETHICS
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Participant information and consent/assent form" document, the 
"Parent(s)/Legal representative information and consent form" document, the list of 
investigators document, the insurance documents, the SmPC or Investigator’s Brochure of 
administered IMPs and NIMPs will be submitted to (an) IEC(s) by the investigator(s) or the 
national coordinator(s) or the sponsor in accordance with local regulations. 
The study will not start in a centre before written approval by corresponding IEC(s) has been 
obtained, the local regulatory requirements have been complied with, and the signature of the 
clinical study protocol of each contractual party involved has been obtained. 
13.2. Study conduct 
The study will be performed in accordance with the ethical principles stated in the 
Declaration of Helsinki 1964, as revised in Fortaleza, 2013 (see Appendix 6) with the GCP 
and with the applicable regulatory requirements. 


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13.3. Participant information and informed consent 
In any case, the participant (and/or his/her legal representative, when required) must be 
informed that he/she is entitled to be informed about the outcome of the study by the 
investigator. 
The investigator or a person designated by him/her is to collect written consent/assent from 
each participant, when of appropriate intellectual maturity and written consent from his/her 
parent(s) (according to local regulations)/legal representative before his/her participation in 
the study. 
Prior to this, each participant in the presence of his/her parent(s)/legal representative should 
be informed by the investigator or his/her delegate to the fullest extent possible about the 
study in language and terms he/she is able to understand. The investigator should also inform 
the parent(s)/legal representative of the objectives, benefits, risks and requirements imposed 
by the study, as well as the nature of IMPs and NIMPs. The participant must be informed that 
he/she has the possibility not to participate in the study and that he/she is free to reconsider 
his/her assent at any time. 
The parent(s)/legal representative of the participant and the participant* will be provided with 
an information and consent/assent form in clear, simple language. The participant and his/her 
parent(s)/legal representative must be allowed ample time to inquire about details of the study 
and to decide whether to participate in the study. 
Two original legal representative information and consent forms must be completed, co-
signed and dated personally by participant’s parent(s)/legal representative and by the person 
responsible for collecting the informed consent. 
Two original participant information and consent/assent forms must be completed, co-signed 
and dated personally by the participant if capable and by the person responsible for collecting 
the informed consent/assent. 
If the parent(s)/legal representative are(is) unable to read, an impartial witness should be 
present during the entire informed consent discussion. The parent(s)/legal representative must 
give consent orally, and if capable of doing so, complete, sign and personally date the 
information and consent form. The witness must then complete, sign and date the form 
together with the person responsible for collecting the informed consent. 
The participant's parent(s)/legal representative will be given one signed original information 
and consent form, and one original information and assent form. The second originals will be 
kept by the investigator. 
A copy of the information and assent/consent form for the participant and his/her 
parent(s)/legal representative in the language(s) of the country is or are given in the 
"Participant information and consent form" document and in the "Parent(s)/Legal 
representative information and consent form" document attached to the protocol. 
* Depending on the age of the minor, two different written information and consent forms may be prepared: one for the participant and one
for his/her parent(s)/legal representative


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13.4. Modification of the information and consent form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version of the information and consent form in the language(s) of the 
country will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IEC has been 
obtained and compliance with the local regulatory requirements, except for an amendment 
required to eliminate an immediate risk to the study participants. 
Each participant affected by the amendment and/or his/her parent(s)/legal representative must 
complete, date and co-sign one, or two if required by local regulation, original(s) of the new 
version of the information and consent form together with the person who collected the 
informed consent (and an independent witness, if applicable). He/She/They will receive one 
signed copy (or original, if required by local regulation) of the amendment to the information 
and consent form(s). The signed original(s) will be kept by the investigator 
14. DATA HANDLING AND RECORD KEEPING
14.1. Study data 
A 21 CRF Part 11-compliant electronic data capture system is going to be used for this study. 
An electronic case report form (e-CRF) is designed to record the data required by the protocol 
and collected by the investigator. 
The e-CRF will be produced by I.R.I.S. in compliance with its specifications. The investigator 
or a designated person from his/her team will be trained for the use of the e-CRF by the 
sponsor. 
Data entry at the investigator’s site will be performed by the investigator or by the designated 
person from his/her team after completion of the participant’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study 
database. 
The investigator or the designated person from his/her team agrees to complete the e-CRF, at 
each participant visit, and all other documents provided by the sponsor (e.g. documents 
relating to the IMP management…). 
Data recorded directly on e-CRF and considered as source data (see section 4.6) must be 
collected immediately in the e-CRF. The other e-CRF forms must be completed as soon as 
possible following each visit. 
All corrections of data on the e-CRF must be made by the investigator or by the designated 
person from his/her team using electronic data clarifications according to the provided 
instructions. All data modification will be recorded using the audit trail feature of Inform 
software, including date, reason for modification and identification of the person who has 
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In order to ensure confidentiality and security of the data, usernames and passwords will be 
used to restrict system access to authorised personnel only, whether resident within the 
investigator’s sites, the sponsor or third parties. 
Data will be verified in accordance with the monitoring strategy defined for the study. After 
comparing these data to the source documents, the monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be answered 
and closed as quickly as possible. 
Data can be frozen during the study after their validation. However, the investigator has the 
possibility to modify a data if deemed necessary via a request to the sponsor. 
After the last visit of the participant, the investigator or co-investigator must attest the 
authenticity of the data collected in the e-CRF by entering his/her user name and password. 
After the data base lock, the investigator or an authorized member of his/her team will have to 
download from the e-CRF an electronic file containing participant data of his/her centre 
for archiving it in the study file (see section 14.3).  
14.2. Data management 
Data are collected via a CRF and stored in a secured database. 
For data collected on the e-CRF, the Clinical Data Management of I.R.I.S. is responsible for 
data processing including data validation performed according to a specification manual 
describing the checks to be carried out. As a result of data validation, data may require some 
changes. An electronic data clarification form is sent to the investigator who is required to 
respond to the query and make any necessary changes to the data. 
For data transferred from central laboratory, the Clinical Data Management of I.R.I.S. is 
responsible for data transfer. Centralised laboratory provide(s) electronic transfer of 
computerised data to the Clinical Data Management of I.R.I.S. Data are transferred according 
to a transfer protocol issued by the I.R.I.S. data manager. 
The Medical Review Department of I.R.I.S. is responsible for data coding including: 
­ medical / surgical history, adverse events and procedures using MedDRA, 
­ medications using World Health Organization, Drug Dictionary (WHO-Drug). 
The coding process is described in a specification manual. 
The investigator ascertains he/she will apply due diligence to avoid protocol deviations. 
Under no circumstances should the investigator contact the sponsor or its representatives 
monitoring the study, if any, to request approval of a protocol deviation, as no deviations are 
permitted. If the investigator feels a protocol deviation would improve the conduct of the 
study this must be considered a protocol amendment, and unless such an amendment is agreed 
upon by the sponsor and approved by the IEC it cannot be implemented. All important 
protocol deviations will be recorded and reported in the clinical study report. 
When data validation is achieved, a review of the data is performed according to the sponsor 
standard operating procedure. When the database has been declared to be complete and 
accurate, it will be locked and the IMP codes will be unblinded and made available for data 
analysis. 


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14.3. Archiving 
The investigator will keep all information relevant to the study for at least 25 years after the 
end of the study, or more if specified by the local regulation.  
At the end of the study, the investigator or an authorized member of his/her team will 
download an electronic copy of each participant’s data from the e-CRF and should keep it in a 
reliable, secure and durable location. The file includes all data and comments reported in the 
e-CRF, the history of all queries and signatures and the full audit trail reports.
The file must include appropriate restrictions (password protection) and adequate protection 
from loss, physical damage or deterioration for the duration of the archiving period. 
15. INSURANCE
I.R.I.S., or any parent company of SERVIER GROUP in charge of the management of
clinical trials, is insured under the liability insurance program subscribed by LES
LABORATOIRES SERVIER to cover its liability as sponsor of clinical trials on a worldwide
basis.
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any 
parent company of SERVIER GROUP will be insured under a local and specific policy in 
strict accordance with any applicable law.  
All relevant insurance documentation is included in the file submitted to any authorities’ 
approval of which is required. 
16. OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND
PUBLICATION POLICY
I.R.I.S., acting as the study sponsor, assumes full responsibilities relating to this function and
retains exclusive property rights over the results of the study, which it may use as it deems fit.
I.R.I.S. will ensure that the key design elements of this protocol will be posted in a publicly
accessible database such as clinicaltrials.gov. In addition, upon study completion and
finalization of the study report, the results of this study will be either submitted for
publication and/or posted in a publicly accessible database of clinical study results.
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end shall be submitted to the sponsor in 
accordance with the guidelines set forth in the applicable publication policy or financial 
agreement.  
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration. 
As the study is a multicentre one, the first publication must be performed only with data 
collected from several centres and analysed under the responsibility of I.R.I.S. The 
investigator commits himself not to publishing or communicating data collected in only one 


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centre or part of the centres before the publication of the complete results of the study, unless 
prior written agreement from the other investigators and I.R.I.S. has been provided. 
Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. 
Researchers can ask for a study protocol, patient-level and/or study-level clinical trial data 
including clinical study reports (CSRs). 
They can ask for all interventional clinical studies: 
­ submitted for new medicines and new indications approved after 1 January 2014 in the 
European Economic Area (EEA) or the United States (US). 
­ Where Servier or an affiliate are the Marketing Authorization Holders (MAH). The date of 
the first Marketing Authorization of the new medicine (or the new indication) in one of the 
EEA Member States will be considered within this scope. 
In addition, Servier’s data sharing policy includes all interventional clinical studies in 
patients: 
­ sponsored by Servier, 
­ with a first patient enrolled as of 1 January 2004 onwards, 
for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for 
which development has been terminated before any Marketing authorization (MA) 
approval 
The datasets generated and/or analysed during the current study will be available upon request 
from www.clinicaltrials.servier.com after the Marketing Authorisation has been granted. 
Summary results and a lay summary will be published on www.clinicaltrials.servier.com 
within 6 months after the end of the study. 
17. ADMINISTRATIVE CLAUSES
17.1. Concerning the sponsor and the investigator 
17.1.1. Persons to inform 
In accordance with local regulations, the investigator and/or the sponsor will inform, the 
Director of the medical institution, the pharmacist involved in the study and the Director of 
the analysis laboratory. 
17.1.2. Substantial protocol amendment and amended protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by the coordinator and the sponsor. 
The substantial protocol amendment must be drafted in accordance with the sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both 
documents must be kept with the initial protocol. 
All substantial amendments and corresponding amended protocols must be sent by the 
investigator(s) or the coordinator(s) or the sponsor, in accordance with local regulations, to 


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the IEC that examined the initial protocol. They can only be implemented after a favourable 
opinion of the IEC has been obtained, local regulatory requirements have been complied with, 
and the amended protocol has been signed, except for a measure required to eliminate an 
immediate risk to the study participants. 
When the submission is performed by the investigator or the coordinator, the latter must 
transmit a copy of IEC’s new written opinion to the sponsor, immediately upon receipt. 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
Competent Authorities in accordance with local regulations. 
17.1.3. Final study report 
The study report will be drafted by Medical Writing Department in compliance with I.R.I.S. 
standard operating procedure. 
The sponsor’s representative and the coordinator must mutually agree on the final version. 
One copy of the final report must be dated and signed by the coordinator and the Director of 
the Center for Therapeutic Innovation. 
The clinical study report, the summary of the results of the clinical trial together with a 
summary that is understandable to a layperson will be submitted where applicable within 6 
months after the end of the clinical trial. 
17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ supply the investigator with adequate and sufficient information concerning the IMPs and 
the NIMPs administered during the study to enable him/her to carry out the study, 
­ supply the investigator with investigator’s brochure if the IMP is not marketed,  
­ obtain any authorisation to perform the study and/or import licence for the IMPs 
administered that may be required by the local authorities before the beginning of the 
study, 
­ provide the coordinator annually, or with another frequency defined by the local 
regulations, with a document describing study progress which is to be sent to the IEC(s). 
­ take all the necessary precautions to maintain the safety of the processed data, in particular 
their confidentiality, their integrity and their availability, by assessing risks identified 
concerning personal data protection. The following measures will be implemented (non 
exhaustive):   
o
Management of authorisation to access to personal data (e-CRF)
o
Identification and authentication measures before accessing personal data (e-CRF)
o
Traceability measures for the access to and modification of personal data (e-CRF)
o
Secured data transfer
o
Time limit for storing personal data
­ handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department…) in order to qualify the security incident (Information 
systems, nature and number of personal data impacted), to define an action plan for 
corrective actions and to notify to relevant person (authority and/or if needed individuals). 


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17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by the sponsor with respect to 
S95014 and study CL2-95014-002 are strictly confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on paper and computer and stored for its sole use relating to its 
activities as the sponsor of clinical trials, in accordance with GCP.  
He/she has a right to access, modify, and delete his/her own personal data by applying to the 
sponsor. 
In case patient wants to exercise his/her rights regarding personal data protection, he/she will 
contact the investigator. The investigator will forward the request to the sponsor (see 
Appendix 7).  
The investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding 
as long as the confidential information has not been disclosed to the public by the sponsor. 
The clinical study protocol given to the investigator may be used by him/her or his/her 
colleagues to obtain the informed consent of study participants. The clinical study protocol as 
well as any information extracted from it must not be disclosed to other parties without the 
written authorisation of the sponsor. 
The investigator must not disclose any information without the prior written consent from 
I.R.I.S., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator commits himself/herself to informing I.R.I.S. prior to 
disclosure of information to these authorities.
A participant screening log and a full identification and enrolment list of each participant will 
be completed and kept in a safe place by the investigator who should agree to provide access 
on site to the auditor and/or the representatives of the Competent Authorities. The information 
will be treated in compliance with professional secrecy. 
The participant screening log must be completed from the moment the investigator checks 
that a participant could potentially take part in the study (by assessment of participant medical 
history during a visit or by examination of the medical file). 
17.3.2. Organisation of the centre 
Every person to whom the investigator delegates under his/her responsibility a part of the 
follow-up of the study (co-investigator, nurse…) and any other person involved in the study 
for this centre (cardiologist, pharmacist…) must figure in the "Organisation of centre" 
document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the centre. 
17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 


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­ to provide his/her dated and signed English Curriculum Vitae (CV) (maximum 2 pages) or 
to complete in English the CV form provided by the sponsor and to send it to the sponsor, 
together with that of his/her co-investigator(s), 
­ to provide a detailed description of the methods, techniques, and investigational 
equipment, and the reference values for the parameters measured, 
­ to provide any other document required by local regulation (e.g. Food & Drug 
Administration 1572 form), 
­ to send, a copy of the IEC’s opinion with details of its composition and the qualifications 
of its constituent members. 
The CVs of other members of the team involved in the study (if possible, in English) will be 
collected during the course of the study (at least, members involved in the participants’ 
medical follow-up/study-related decision process and persons involved in the measurement of 
main assessment criteria). 
18. REFERENCES
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Asselin BL. The three asparaginases: Comparative pharmacology and optimal use in childhood leukemia. Adv 
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Esparza SD, Sakamoto KM. Topics in pediatric leukemia—acute lymphoblastic leukemia. MedGenMed 
2005;7:23 [PE0159181] 
Heo YA et al. Pegaspargase: A Review in Acute Lymphoblastic Leukaemia. Drugs (2019) 79:767–777 
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Hoelzer D, Bassan R, Dombret H, et al. Acute lymphoblastic leukaemia in adult patients: ESMO clinical practice 
guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):v69–82. [PE0128919] 
Kaprin, V. Starinsky, G. Petrova “Malignant neoplasms in Russia in 2018 (morbidity and mortality)”, published 
in Moscow, 2019 
Masetti R; Pession. A First-line treatment of acute lymphoblastic leukemia with pegasparaginase. Biologics. 
2009; 3:359-368. [PE0151695] 
National Comprehensive Cancer Network (NCCN). Acute Lymphoblastic Leukemia. 2020 [PE0159180] 
Noone AM; Howlader N; Krapcho M; Miller D; Brest A; Yu M et al. 2018. SEER Cancer Statistics Review, 
1975-2015 - Section 29: Childhood Cancer by the ICCC [PE0153306] 
Silverman LB et al. Intravenous PEG-asparaginase during remission induction in children and adolescents with 
newly diagnosed acute lymphoblastic leukemia. Blood 2010;115:1351-1353 [PE0151917] 
Tong WH, Pieters R, Kaspers GJ, et al. A prospective study on drug monitoring of PEGasparaginase and 
Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 
2014;123(13):2026–33. [PE0151923] 
Van der Sluis IM et al. Consensus expert recommendations for identification and management of asparaginase 
hypersensitivity and silent inactivation. Haematologica. 2016; 101(3):279-285. [PE0155838] 
Vrooman LM et al. Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute 
lymphoblastic leukemia/lymphoma: Results of DFCI 11-001. Journal of Clinical Oncology 37, no. 15_suppl 
(May 20, 2019) 10006-10006 [PE0153989] 


S95014 
Amended clinical study protocol CL2-95014-002– Final version 
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 (c) I.R.I.S. - 02 December 2020 - Confidential 
Other regulatory references: 
ICH Topic E6 – Guideline for Good Clinical Practice: Consolidated guideline finalised (step 4) in June 1996. 
Adopted by CPMP, July 96, issued as CPMP/ICH/135/95/step 5, post step errata, July 2002. 
ICH Topic E9 – Statistical Principles for Clinical Trials: Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, issued 
as CPMP/ICH/377/95. 
Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’), (2011/C 172/01) 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials 
on medicinal products for human use. 
Clinical Investigator's Brochure - ONCASPAR® (pegaspargase) (PEG-L-asparaginase, EZ-002, SHP 674) - 
Version n° 5 of 21 October 2020 [NP40790]  
19. APPENDICES
Appendix 1: ALL-MB 2015 protocol 
Appendix 2: NCCN guidelines 2020  
Appendix 3: Patient performance status 
Appendix 4: Hepatotoxicity form 
Appendix 5: Trial Conduct During National or International Public Health Emergency 
Appendix 6: World Medical Association Declaration of Helsinki 
Appendix 7: Instructions to investigator for handling data rights requests 

SAP_001.pdf: 
Document title 
STATISTICAL ANALYSIS PLAN 
Study title 
A multicentre, Phase II Randomized study, Open-label, with 2-
arm Parallel Group, comparing the pharmacokinetics of the 
Liquid and the Lyophilized Formulations of pegaspargase 
(S95014) in Treatment of Paediatric Patients with Newly-
Diagnosed Acute Lymphoblastic Leukemia (ALL) 
Test drug code 
S95014 / pegaspargase / Oncaspar® 
Indication 
Acute Lymphoblastic Leukemia 
Development phase 
Phase II 
Protocol code 
CL2-95014-002 
EudraCT Number 
2020-004894-29 
Universal Trial Number 
Not applicable 
Sponsor 
I.R.I.S.
Date of the document 
23 May 2022 
Version of the document 
Version 1.0 
CONFIDENTIAL 
I.R.I.S. 
INSTITUT DE RECHERCHES INTERNATIONALE$ SEJRVIER 
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Table of contents 
1. INTRODUCTION ............................................................................................................... 5 
1.1. Study objectives ................................................................................................................ 5 
1.1.1. Primary objective............................................................................................................ 5 
1.1.2. Secondary objectives ...................................................................................................... 5 
1.2. Study design ...................................................................................................................... 5 
1.2.1. Study plan ....................................................................................................................... 5 
1.2.2. Type of randomisation .................................................................................................... 6 
1.3. Determination of sample size ........................................................................................... 6 
2. ANALYSIS SETS / TREATMENT GROUPS .................................................................. 7 
2.1. Analysis sets ..................................................................................................................... 7 
2.2. Treatment groups .............................................................................................................. 7 
3. STATISTICAL METHODS ............................................................................................... 8 
3.1. General considerations ...................................................................................................... 8 
3.1.1. Descriptive statistics ....................................................................................................... 8 
3.1.2. General definitions ......................................................................................................... 8 
3.2. Handling of Missing, Unused, and Spurious Data ............................................................ 8 
3.3. Disposition and baseline characteristics ........................................................................... 9 
3.3.1. Disposition of subjects ................................................................................................... 9 
3.3.2. Protocol deviations ......................................................................................................... 9 
3.3.3. Demographic data and other baseline characteristics ..................................................... 9 
3.4. Treatments of subjects .................................................................................................... 10 
3.4.1. Extent of exposure ........................................................................................................ 10 
3.4.2. Concomitant treatments ................................................................................................ 10 
3.5. Pharmacokinetics analysis .............................................................................................. 10 
3.6. Safety analysis ................................................................................................................ 11 
3.6.1. Adverse Events ............................................................................................................. 11 
3.6.2. Other Safety Evaluations .............................................................................................. 12 
3.7. Analysis of Plasma Asparaginase Activity ..................................................................... 13 
3.8. Immunogenicity Analysis ............................................................................................... 13 
4. INTERIM ANALYSIS ...................................................................................................... 13 
5. APPENDICES .................................................................................................................... 14 
6. CHANGES FROM THE PLANNED STATISTICAL ANALYSIS ............................. 14 
7. REFERENCES .................................................................................................................. 14 
 
 
 
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List of figures 
Figure (1.2.1) 1 - Study plan ...................................................................................................... 6 
 
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List of abbreviations 
ADA 
: Anti-Drug Antibodies 
AE 
: Adverse Event 
AEOSI 
: Adverse Event Of Special Interest 
ALL 
: Acute Lymphoblastic Leukemia 
ALT 
: Alanine aminotransferase 
ANOVA 
: Analysis of Variance 
AUC 
: Area Under the Curve 
AST 
: Aspartate aminotransferase 
BMI 
: Body Mass Index 
BSA 
: Body Surface Area 
CBI 
: Central Business Intelligence 
CI 
: Confidence Interval 
Cmax 
: maximum Concentration 
CoV 
: Coefficient of Variation 
CTC 
: Common Terminology Criteria 
CTCAE 
: Common Terminology Criteria for Adverse Events 
DAP 
: Data Analysis Plan 
ECG 
: ElectroCardioGram 
FAS 
: Full Analysis Set 
GMR 
: Geometric Mean Ratio 
IAS 
: Immunogenicity Analysis Set 
IMP 
: Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial (test drug / placebo / reference product) 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
IRS 
: Interactive Response System 
MedDRA 
: Medical Dictionary for Regulatory Activities 
NCI 
: National Cancer Institute 
PAA 
: Plasma Asparaginase Activity 
PEG 
: PolyEthylene Glycol 
PK 
: PharmacoKinetics 
PKAS 
: Pharmacokinetic Analysis Set 
RDI 
: Relative Dose Intensity 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SAS 
: Safety Analysis Set 
SD 
: Standard Deviation 
TEAE 
: Treatment Emergent Adverse Event 
TLG 
: Tables, Listings and Graphs 
%CV 
: Coefficient of Variation in percent 
 
 
 
 
 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) details the planned analyses to be performed, in accordance 
with the main characteristics of the study protocol v2.0, dated on December 2nd, 2020, and the 
non substantial Protocol Amendment, dated on Apr 7th, 2021. The templates for Tables, 
Listings and Graphs (TLG) are described in a separate document. 
1.1. Study objectives 
1.1.1. Primary objective 
To compare the pharmacokinetics (PK) of both lyophilized and liquid S95014 formulations 
during the induction phase after a single IV dose in newly diagnosed paediatric patients with 
ALL  
1.1.2. Secondary objectives 
­ To describe the PK of S95014 after administration of either lyophilized or liquid formulation  
­ To evaluate the occurrence of treatment emergent adverse events (TEAEs) including serious 
adverse events (SAEs), regardless of causality and severity, based on National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 
­ To evaluate the achievement of plasma asparaginase activity (PAA) of ≥0.1 U/mL after the 
administration of either lyophilized or liquid S95014  
­ To assess the immunogenicity of both lyophilized and liquid S95014 formulations  
1.2. Study design 
This is a multicentre, national, randomized, open-label, phase II clinical study comparing the 
pharmacokinetics of lyophilized and liquid Pegaspargase (Oncaspar®, S95014) formulations 
in the treatment of newly diagnosed, untreated pediatric patients with ALL. 
1.2.1. Study plan 
Each patient will be randomly assigned (1:1) to either lyophilized (arm 1) or liquid (arm 2) 
S95014 intravenously at the dose of 2500 U/m² at Day 3, in combination with other backbone 
chemotherapy agents as per local practice. 
The study duration will be approximately 1.5 month, including the screening (14 days) and the 
treatment period consisting of the induction phase (approximately 30 days). After completing 
the induction phase, patient will be discontinued from the study and, provided that the 
inclusion/non-inclusion criteria are fulfilled, will be proposed to enter into a roll-over study 
(CL2-95014-003) for the consolidation phase. 
The study will be divided into the following periods for each participant: 
­ Screening visit (up to 14 days prior to inclusion): to obtain informed consent and check 
the screening/non-screening criteria. 
­ Screening period (Day -14 to Day -1): to check the eligibility of the patient to be included  
in the study within 14 days prior to the inclusion. 
­ Inclusion visit (Day 0): to check inclusion/non-inclusion criteria and to confirm inclusion 
of the patient in the study 
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­ Randomization (Day 0): the day of inclusion visit (i.e. Day 0), included subjects will be 
randomly assigned to one of the two treatment groups: 
 Lyophilized S95014 (arm 1) 
 Liquid S95014 (arm 2) 
­ Infusion (Day 3): the day of S95014 infusion, based on randomized treatment group. 
­ Treatment period: treatment period will start from the day of S95014 infusion, 
corresponding to Day 3 of the induction phase, until the withdrawal/end-of-study visit.  
­ Withdrawal/End-of-study visit: at least 30 days after S95014 infusion (i.e. Day 33) and 
before starting the consolidation phase. During the withdrawal/end-of-study visit, subjects 
will be proposed to participate in a roll-over study (CL2-95014-003) for the consolidation 
phase using lyophilized S95014 in combination with backbone regimen as per ALL-MB 
2015 protocol. 
The study plan is shown in Figure (1.2.1) 1. 
Figure (1.2.1) 1 - Study plan 
 
1.2.2. Type of randomisation 
The treatment groups will be allocated via IRS using a central randomization (1:1) to either 
lyophilized S95014 (arm 1) or liquid S95014 (arm 2) of the induction phase.  
1.3. Determination of sample size 
This study is a two-arm parallel 1:1 randomized trial to evaluate the PK comparability between 
liquid and lyophilized S95014 formulations. For both AUC and Cmax, the coefficient of 
variation (CoV) of 0.30 is assumed based on the estimation of CoV for liquid S95014 from a 
previous study (Angiolillo, 2014). It is also reasonable to assume a geometric mean ratio (GMR) 
of 100% for Cmax and AUC, since no impact of an absorption phase is expected because both 
formulations are delivered intravenously. In addition, the CMC investigations have shown that 
once the lyophilised formulation is reconstituted, the characteristics of the solution are 
comparable to the ones of the liquid formulation. Assuming a CoV of 0.30 and a true GMR of 
100%, a total of 78 evaluable subjects (39 subjects per arm) will provide approximately 90% 
power to establish the PK comparability. Assuming that 10% of the included subjects could not 
r 
Screening 
period 
Lyophilized (arm 1) 
or Liquid (arm 2) 
S95014 infusion 
l 
D3 
D10 
® 
r 
lmmunogenicity 
Screening 
visit 
ICF signed 
assessment 
Inclusion 
R: randomization 
D: Day 
visit 
D17 
D28 
End of study 
Wit hdrawal 
D36 
CL2-95014-003 
roll-over study 
Induction phase 
Consolidation phase 
1 
1 
lmmunogenicity 
lmmunogenicity 
assessment 
assessment 
PK assessment (D3-D28) 
PAA assessment (D10-D28) 
Safety assessment 
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be evaluable (e.g. missing PK timepoint etc.), 88 subjects are expected to be included to allow 
78 evaluable subjects. 
2. ANALYSIS SETS / TREATMENT GROUPS 
2.1. Analysis sets  
Full Analysis Set 
The full analysis set (FAS) will consist of all subjects who have been randomized in the study. 
Subjects will be classified according to their assigned treatment arm. 
 
Safety Analysis Set  
The safety analysis set (SAS) is defined as the set of all subjects who have received at least one 
dose of S95014 in the study. Subjects will be classified according to treatment received. The 
safety endpoints will be analysed in the safety analysis set, unless otherwise specified. 
 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) will include all subjects who have received at least 
one dose of IMP and are evaluable for PK analysis. The PK dataset will include only the 
subjects who had enough samples collected to provide interpretable PK results with no 
deviations that might have affected the PK interpretation (e.g. infusion interrupted for any 
reason, deviation in the theoretical administered dose > 10%, at least one missing PK sample 
during the 48 first hours, ≥ 2 missing PK samples after the 48-hour time point). The ADA-
positive subjects will be a priori included in the PKAS since no impact was identified based on 
the population PK model. Nevertheless, if any evidence of such an impact can be identified in 
the study, a second PKAS will be defined that will include the subjects for whom none of the 
ADA assessment time points is positive. 
 
Immunogenicity Analysis Set 
The immunogenicity analysis set (IAS) will include all subjects who have received at least one 
dose of IMP and have at least one post-dose sample evaluable for immunogenicity testing. 
2.2. Treatment groups 
S95014 liquid (reference drug) and S95014 lyophilizate (test drug) are both IMPs. 
­ Arm 1: lyophilized S95014 reconstituted will provide 5 mL of extractable volume with the 
concentration of 750 U/mL. The vial of lyophilized powder (3.750 U/vial) is reconstituted 
with 5.2 mL of SWFI to obtain a 750 U/mL solution for single use. 
­ Arm 2: liquid S95014 is provided as 3.750 U per 5 mL solution in a single use vial to obtain 
a 750 U/mL solution for single use.  
S95014 (either liquid or lyophilized) will be intravenously administered over 1 hour at the dose 
of 2500 U/m2 at Day 3 of the induction phase. Subjects will receive other backbone 
chemotherapy agents as per ALL-MB 2015 protocol. 
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3. STATISTICAL METHODS 
3.1. General considerations 
All data processing, summarization, and analyses will utilize SAS® software package, Version 
9.3, unless otherwise specified. 
3.1.1. Descriptive statistics 
For qualitative data, number of observed values, number and percentage of subjects per class 
will be presented. Unless otherwise specified in the TLG, no class "Missing" is considered. 
For quantitative data, number of observed values, mean, standard deviation, median, first and 
third quartiles, minimum and maximum will be presented. For lognormal-distributed PK 
parameters, coefficient of variation (CoV), geometric mean and geometric CoV will also be 
presented. 
3.1.2. General definitions 
Unless specified otherwise in section 3.3 to 3.5, the following definitions will be considered: 
­ 
Analysable value will be defined as any non-missing value. 
­ 
Baseline value will be defined as the last analysable value prior to the first IMP intake 
(i.e. before or the same date as the first IMP intake date). 
­ 
Post-baseline value will be defined as any value recorded at a given timepoint after 
baseline. 
­ 
Change from baseline will be defined as the arithmetic difference between a post-
baseline value and the baseline value for a given variable at a given time point. 
3.2. 
Handling of Missing, Unused, and Spurious Data  
No specific imputation method will be used for missing data, unless otherwise specified. 
Adverse events (AEs) 
­ Handling of unknown causality assessment: 
o 
If a subject experience an AE with a missing causality assessment, the relationship of 
the AE will be counted as “related”. 
­ Handling of unknown severity grades: 
o 
If a subject experiences more than one AE categorized under the same preferred term, 
one of them is categorized as “severe” and one of them is categorized as “unknown”, 
the severity of this AE should be counted as “severe”. 
o 
If a subject experiences more than one AE categorized under the same preferred term, 
one of them is categorized as “mild” or “moderate” and one of them is categorized as 
“unknown”, the severity of this AE should be counted as “unknown”. A column “UNK” 
should be inserted for those AEs at the end of the table (before the “Total” column if 
applicable). 
 
Immunogenicity 
Missing baseline anti-drug antibody results will be imputed as negative. 
 
Missing dates 
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If no specific management of dates is defined, missing information is substituted as shown 
below:  
Table (3.1.2) 1 - Substitution rules of dates if no specific management is defined 
Date to substitute 
Substituted date  
Date 
../mmm/yyyy 
01/mmm/yyyy 
../…/yyyy 
01/JAN/yyyy 
../.../…. 
No substitution 
Note: 
../mmm/yyyy = missing day 
../.../ yyyy = missing day and month 
../.../.... = missing date 
 
3.3. Disposition and baseline characteristics  
Disposition of subjects and baseline characteristics will be described by treatment group, to 
assess their comparability, and overall. 
3.3.1. Disposition of subjects 
Subject disposition will be tabulated for all subjects by summarizing the number and percentage 
of subjects who are included in each analysis set, randomized, completed study treatment, 
discontinued from the study and by the primary reason for discontinuation. 
A listing will present dates of study discontinuation and the primary reason, if applicable for 
each subject. 
3.3.2. Protocol deviations 
Important protocol deviations will be summarized for the full analysis set by treatment group, 
using the number and percentage of subjects who had each type of deviation for the SAS. 
COVID-19 related protocol deviation will be also summarized. Protocol deviations will be 
reviewed by the sponsor prior to the database lock. In addition, these protocol deviations will 
be listed: 
 Inclusion/Exclusion criteria not respected 
 Study Withdrawal criteria not respected 
 Study Treatment: incorrect dose or wrong treatment 
 Primary Endpoint interpretation may be compromised 
 Safety/Rights affected 
3.3.3. Demographic data and other baseline characteristics 
Demographic and baseline measurements will be summarized for the safety analysis set and the 
pharmacokinetic analysis set, using standard descriptive summaries or categorical summaries, 
as appropriate. In addition to the summary tables, a listing will be provided for all demographic 
and baseline characteristics data. In addition, listing of medical history will be provided. 
The following baseline characteristics will be summarized based on descriptive statistics: 
 Age at screening (years; if not available, then it will be calculated as the biggest integer 
<= [(ICF date – date of birth + 1) / 365.25]) 
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o As continuous variable 
o By categories (age <10, 10 - <16, and >= 16 years) 
 Sex 
 Race 
 Ethnicity 
 Height (cm) 
 Weight (kg) 
 Body Mass Index (BMI (kg/m2) = weight (kg) / height (m)2) 
 Body Surface Area (BSA(m2) = sqrt (height (cm) x weight (kg) / 3600)) 
Baseline disease characteristics will be separately tabulated in a similar fashion for the 
following variables: 
 ALL subtype and therapeutic group (B-Cell type Acute Leukemia (therapeutic groups: 
A/B/C/D1/D2/F/1221-SR/1221-IR)/E / T-Cell type Acute Leukemia (therapeutic 
groups: F/T-SRG/T-ImRG/T-HRG)  
 
3.4. Treatments of subjects 
3.4.1. Extent of exposure 
Each patient will receive either lyophilized (arm 1) or liquid (arm 2) S95014, per the 
randomization at D000, intravenously over 1-hour at the dose of 2500 U/m² at Day 003 during 
the induction phase. Exposure to test drug for each subject will be listed. The following metrics 
will be summarized: 
 Total exposure (U) 
 Relative dose intensity (RDI): total exposure (U) / (2500 U/m2 x BSA) 
The safety analysis set will be used for exposure analysis. Listings of all dose 
change/interruption and reasons will be produced. 
3.4.2. Concomitant treatments 
Concomitant medication for each subject in the safety analysis set will be listed.  
3.5. Pharmacokinetics analysis 
The pharmacokinetic analysis will be performed on the Pharmacokinetic Analysis Set (PKAS). 
The PKAS is defined as all included participants having completed the treatment period without 
deviation affecting pharmacokinetic interpretation.  
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Final analysis will be performed after the database lock and the electronic transfer of PK data 
(i.e. PAA). The dataset needed for final analysis will be prepared by extraction under the 
supervision of Clinical Data Management Department from the I.R.I.S database.  
A non-compartmental pharmacokinetic analysis will be performed on the individual PAA-time 
profiles, using the actual administration and sampling times after IMP administration. 
Calculated PK parameters will be described according to a separate Data Analysis Plan (DAP) 
such as: area under the PAA-time curve from time 0 to the time of the last observed non-zero 
PAA (AUC0-Tlast); area under the PAA-time curve from time 0 extrapolated to infinity (AUCinf); 
percent of AUCinf extrapolated (AUC%ext) ; maximum observed PAA (Cmax); time to maximum 
PAA (Tmax); observed PAA 14 days post-dose(Cday 14); last observed PAA (Clast); time to last 
observed PAA (Tlast); terminal half-life (T1/2). The above PK parameters will be calculated for 
each patient (details of the PK parameter derivation will be specified in a separate document) 
and the corresponding descriptive statistics of PK parameters will be tabulated by treatment 
group (e.g. number of subjects, arithmetic mean, SD, geometric mean, geometric CoV, median, 
min, max). 
Descriptive statistics of PAA (e.g. number of subjects, arithmetic mean, geometric mean, % 
coefficient of variation [%CV], SD, minimum, median, and maximum) will be also calculated 
and tabulated per nominal sampling time by treatment group. Plasma asparaginase activity over 
time will be plotted in semilogarithmic and linear formats as mean  SD and as median (Q1, 
Q3), using the nominal timepoints. 
Bioequivalence tests will be used to compare the primary endpoints (AUC and Cmax) in 
lyophilized formulation versus liquid formulation using the PKAS. Individual values of Cmax, 
AUC0-Tlast and AUCinf will be logarithmically transformed prior to statistical analysis. An 
additional comparison will also be performed on Cday 14 for information purpose. To be specific, 
an analysis of variance (ANOVA) will be performed for the natural logarithms of PK 
parameters (AUC0-Tlast, AUCinf, Cmax and Cday14). The ANOVA model will include fixed effect 
for formulation. The two one-sided tests procedure will be performed on the geometric mean 
ratio (GMR) between test (lyophilized pegaspargase) and reference (liquid pegaspargase) 
treatments. This will be done via a 90% confidence interval for the ratio obtained in the 
framework of the ANOVA for the logarithms. The confidence interval will be obtained by 
exponentiation of the upper and lower 90% confidence limits for the difference of logarithm 
means. PK comparability between the test treatment and the reference treatment will be 
concluded if the 90% confidence interval for AUC and Cmax GMR is within the [80.00%; 
125.00%] range.  
Exploratory analysis may be performed to evaluate potential covariates impacting the PK 
parameters. 
3.6. Safety analysis 
All subjects included in the safety analyses will be evaluated by the actual treatment arms unless 
otherwise specified. 
3.6.1. Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any untoward medical occurrence in a 
subject who received IMP, which occurs within the period from the S95014 Infusion (i.e. Day 3), 
until the withdrawal/end-of-study visit, which is at least 30 days after S95014 infusion (i.e. Day 
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33) and before starting the consolidation phase. TEAE will be assessed according to the 
National Cancer Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE) 
v5.0. Laboratory abnormalities will be classified into Common Terminology Criteria (CTC) 
grade according to CTCAE v5.0 and will be reported as adverse events.  
 
Adverse events will be summarized in hierarchical tables, presenting the number and 
percentage of subjects having at least one AE, and having at least one AE in each primary 
system organ class and for each preferred term using MedDRA coding. AEs will be sorted by 
descending frequency, and alphabetically where frequency is tied. Such summaries will be 
produced for all AEs, serious adverse events (SAEs), grades 3 or 4 AEs, AEs leading to study 
discontinuation, and AEs leading to dose-adjustment or interruption of any of the drugs of the 
treatment. All of these summaries will be by system organ class, preferred term, treatment group 
and, in some case, maximum grade. Most of the summaries will be produced twice, once for all 
events regardless of study treatment relationship, and once for events suspected to be study 
treatment related. All deaths will be listed, and separate summaries will be produced by 
treatment.  
 
All adverse events will be listed, and any other information collected (e.g., start/end dates and 
duration of adverse event, severity or relatedness to study medication or backbone therapies) 
will be listed as appropriate.  
 
Adverse events of special interest (AEOSI) will be summarized separately. AEOSI include: 
 Grade ≥ 3 ALT/AST increase or grade ≥ 3 hyperbilirubinemia 
 Grade ≥ 3 haemorrhage or grade ≥ 3 thromboembolic events 
 Grade ≥ 3 pancreatitis 
 Grade ≥ 3 hypersensitivity 
 
All such events will be identified prior to database lock.  
3.6.2. Other Safety Evaluations 
Descriptive statistics of laboratory parameters and continuous variables of vital signs will be 
calculated by treatment group for each time point. Shift tables for qualitative urinalysis results 
at each time point after the start of administration will be created. Height, weight, body surface 
area (BSA) and body mass index (BMI) will be summarized over visit by treatment group.   
 
Shift tables will be provided for laboratory parameters to compare a subject’s baseline 
laboratory evaluation relative to the worst value during the treatment period using Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 grades. In addition, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. Subjects with abnormal laboratory values will be listed and values outside the normal 
ranges will be flagged. 
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3.7. Analysis of Plasma Asparaginase Activity  
Observed individual Plasma Asparaginase Activity (PAA) level 7 days (Day 10), 14 days (Day 
17), 18 days (Day 21) and 25 days (Day 28) after administration of either liquid or lyophilized 
S95014 will be tabulated by treatment group together with descriptive statistics (Arithmetic 
mean, SD, geometric mean, geometric CV, median, min, max).  
 
The number and proportion of subjects achieving a PAA of ≥ 0.1 U/mL after the administration 
of either liquid or lyophilized S95014 among subjects with evaluable Day 10, Day 17, Day 21 
and Day 28 PAA data will be summarized by treatment group along with a 2-sided 95% 
Clopper-Pearson confidence interval (CI).  
3.8. Immunogenicity Analysis 
The immunogenicity analysis will be performed on the Immunogenicity Analysis Set (IAS). 
The assessment of anti-drug antibodies includes binding and neutralizing antibodies to S95014 
and binding anti-PEG antibodies.  
 
The number and proportion of subjects in the immunogenicity analysis set having anti S95014 
± anti-PEG antibodies at pre-dose, and 14 and 25 days (i.e. Day 17 and Day 28) after the 
administration of either liquid or lyophilized S95014 during the induction phase will be 
summarized by treatment group.  
Results will be reported as follows: 
­ Pre-existing anti-S95014 or anti-PEG antibodies: number and proportion of samples 
confirmed positive at baseline.  
­ Seroconversion upon treatment: number and proportion of samples converted from negative 
at baseline to positive at Day 17 and Day 28. If a confirmed positive sample at baseline has 
titer increase at Day 17 or Day 28 by at least 4-fold (boosted ADA responses) then it will be 
included within the seroconverters. If a patient was negative at baseline, and ended up with 
a positive titer of “2” for example, post-treatment, this case was considered as a 
seroconversion despite the fact that the titer was not a 4 fold rise. 
On a case-by-case approach, the impact of positive anti S95014 and anti-PEG antibodies will 
be investigated: 
­ On the pharmacokinetics through the temporal association of antibodies with the loss of 
asparaginase activity (neutralizing antibodies) 
­ On the safety through the temporal relationship with treatment-emergent hypersensitivity 
and anaphylactic reactions. 
A patient with missing baseline will be considered as negative baseline to be conservative. 
4. INTERIM ANALYSIS 
 
No interim analysis is planned for this study. 
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S95014 
Statistical Analysis Plan CL2-95014-002 Version 1.0 
® I.R.I.S. – 23 May 2022 - Confidential 
 
 
5. APPENDICES 
6. CHANGES FROM THE PLANNED STATISTICAL ANALYSIS  
Not applicable. 
7. REFERENCES 
Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, G astier-Foster JM, et al. Pharmacokinetic and 
pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients 
with acute lymphoblastic leukemia: Results from Children´s Oncology Group Study AALL07P4. J Clin Oncol 
2014; 32: 3874-82 [PE0150550] 
 
 
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