Clinical trial NCT04629443
Conditions: Acute Myeloid Leukaemia
Keywords: Acute Myeloid Leukaemia Oncology Mcl-1 inhibitor Azacitidine Combination Phase I/II International Safety Maximum tolerated dose
Sponsor: Institut de Recherches Internationales Servier
Start date: 2021-02-17; Completion date: 2023-08-25
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety, tolerability and clinical activity of the combination S64315 with azacitidine in patients with acute myeloid leukaemia.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: S 64315 (also referred as MIK665) and azacitidine
Intervention descriptions: intervention 1: The combination treatment at the planned doses may be preceded by a 2-week Lead-In Dose period of S64315 (fixed dose) administered via intravenous (IV) infusion over at least 2 hours.

During the combination treatment period S64315 will be administered according to a dose escalation scheme starting at 50 mg up to 250 mg might be explored. The schedule will be a 21-day cycle with a weekly regimen for S64315 and a daily regimen of azacitidine administered at 75 mg/m² via subcutaneous (SC) injection for 7 days from D1 to D7 of each cycle followed by a rest period of 21 days.

Protocol documents:
Prot_000.pdf: 
  
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
Phase I/II, international, multicentre, open-label, non-
randomised, non-comparative study evaluating the safety, 
tolerability and clinical activity of intravenously administered 
S64315, a selective Mcl-1 inhibitor, in combination with 
azacitidine in patients with acute myeloid leukaemia (AML) 
Study public title 
Phase I/II trial of S64315 plus azacitidine in acute myeloid 
leukaemia 
Test drug code 
S64315 
Indication 
Acute Myeloid Leukaemia (AML) 
Development phase 
Phase I/II 
Protocol code 
CL1-64315-004 
EudraCT Number 
2019-004896-38 
Universal Trial Number 
Not applicable 
Other register number 
(ISRCTN, CT. gov…) 
NCT04629443 
Investigational New Drug 
Application Number 
136541 
Sponsor 
I.R.I.S.
International Coordinator 
 
Unité Hématologie 2 et Unité ETOH, Département 
d’Hématologie, Institut Paoli-Calmettes 
232, boulevard Sainte Marguerite 
13009 Marseille - FRANCE 
Date of the document 
14 October 2022  
Version of the document 
Final Version 
Version number 
5.0 
Substantial Amendment(s) 
integrated 
No. 
Final version date 
Countries concerned 
1 
22 February 2021 
ALL 
2 
25 November 2021 
ALL 
3 
12 April 2022 
ALL 
4 
14 October 2022 
ALL 
CONFIDENTIAL 
IRIS 
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














S64315 
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Name of the sponsor: 
I.R.I.S. 
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
­ To explore PK/PD relationships for safety and activity 
­ To explore relationships between DNA polymorphism for proteins involved in ADME and PK parameter 
variability 
 
Arm B objectives 
 
 Dose escalation phase I part 
Primary objective 
­ To determine the safety profile and tolerability 
 
 in patients with AML 
Secondary objectives 
­ To determine the PK profile of 
, 
and potential metabolites 
­ To evaluate the anti-leukemic activity of 
 
Exploratory objectives 
­ Exploratory objectives for Arm B will be further defined. 
Methodology: 
This phase I/II trial is designed as follows: 
- 
Arm A: evaluating the combination of S64315 with azacitidine in the frame of a phase I/II trial and designed 
in two parts: 
• A dose escalation phase I part: a Bayesian logistic regression model (BLRM) with escalation with 
overdose control (EWOC) will be used to guide the dose escalation of the combination. 
• An expansion phase II part with two sub-arms A1 and A2 previously described. A Bayesian two-stage 
adaptive design with one interim analysis for futility will be performed in each sub-arm. 
- Arm B: 
in the frame of a dose 
escalation phase I part. This arm will also be supported by a BLRM with EWOC. 
 
Dose escalation methodology and dose-limiting toxicity (DLT) assessment in Arm A 
The BLRM will be used to estimate the MTD(s) and/or the RP2D based on the occurrence of DLT (defined in 
section 4.1.3.5), including the S64315 lead-in dose (LID) period and the first cycle of treatment. 
Toxicities are assessed according to NCI-CTCAE v5.0. 
The MTD is defined as the highest dosage of S64315 in combination with azacitidine that is unlikely (< 25% 
posterior probability) to cause DLT in more than 33% of the treated patients up to the end of cycle 1. A maximum 
of 6 DLT-evaluable patients may be initially enrolled at a dose level, and a minimum of 3 DLT-evaluable patients 
must be treated at a given dose level before a new higher dose level may be evaluated. More than 6 DLT-
evaluable patients may be treated in a cohort at dose levels considered safe according to the BLRM with overdose 
control in order to better characterize the safety, tolerability, PK, PD, or preliminary clinical activity of S64315 
in combination with azacitidine. A minimum of 6 DLT-evaluable patients must have been evaluated at the dose 
level considered to be the MTD, and before treating patients with this dose in the Phase II part of the study. 
Only the dose of S64315 will be escalated. The first S64315 weekly full tested dose will be 50 mg; azacitidine 
will be administered at a fixed dose (75 mg/m²/day for 7 days) in each cycle of treatment. A panel of S64315 
doses from 25 mg (dose -1) to 250 mg may be tested according to the dose allocation of the BLRM. Intermediate 
doses may be proposed depending on available results during the study. 


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Name of the sponsor: 
I.R.I.S. 
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
Before testing a new dose level, an EoC meeting between the sponsor and the investigators will take place to 
discuss the DLTs, overall safety, PK, PD anti-leukemic activity observed in all patients, and to decide jointly 
the next dose level to be tested. Increments will not exceed 100% of the previous dose. A DSMB will review the 
data before each EoC meeting and provide recommendations. 
For more details, see section 10.2. 
 
Expansion phase II part methodology 
The multi sub-arm expansion phase II part will start once the RP2D (MTD or suitable lower dose) of the 
combination Arm A has been determined during the dose escalation phase I part. A Bayesian two-stage design 
with one interim analysis for futility will guide the decision for each sub-arm and will be divided into two stages: 
stage 1 and stage 2. 
During stage 1, patients will be enrolled and treated at the corresponding RP2D. At the end of stage 1, a Bayesian 
interim analysis for futility will be performed based on CR rate assessment. 
According to futility interim analysis result in each sub-arm (A1 and A2), recruitment could be: 
­ Stopped, if results on CR rate are considered futile 
­ Continued if results on CR rate are considered not futile. In that case, one additional cohort of patients will 
be enrolled in stage 2 until the predefined end of study. 
For more details, see section 10.3. 
Safety data will be reviewed on an ongoing basis during dose expansion as described in section 10.3.2. 
Number of included patients 
Arm A 
­ Dose escalation phase I part: approximately 30 patients 
­ Expansion phase II part: approximately 50 patients per sub-arm (up to 100 overall) 
Arm B 
The number of patients will be further defined. 
Diagnosis and main criteria for inclusion 
The criteria for dose escalation phase I part of Arm A are defined hereafter and should be adapted for expansion 
phase II part (sub-arms A1 and A2) according to results observed in the dose escalation phase I part. The criteria 
will be defined later for Arm B according to the results of Arm A. 
Screening criteria 
Demographic characteristics 
1. Patients aged ≥ 18 years 
Medical and therapeutic criteria 
2. a. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML 
as defined by WHO 2016 classification (Arber, 2016) excluding acute promyelocytic leukaemia (APL, 
French-American-British M3 classification) with: 
- 
relapsed or refractory disease and without established alternative therapy or 
- 
secondary to MDS and without established alternative therapy  
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Appendix 3) 
Informed consent 
4. Written informed consent obtained prior to any study-specific procedure as described in section 13.3 


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I.R.I.S. 
Individual 
Study 
Table 
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Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
Non screening criteria 
Medical and therapeutic criteria 
5. Previous myeloproliferative syndrome (MPS) 
6. Criterion deleted in Substantial Amendment #1 (Amended Protocol V. 2.0) 
7. Patients previously treated with any Mcl-1 inhibitor 
General criteria 
8. Pregnant and lactating women 
9. Unlikely to cooperate in the study  
10. Participation in another interventional study requiring investigational treatment administration at the 
same time or within 2 weeks or at least 5 half-lives (whichever is longer) prior to the first IMP 
administration; participation in non-interventional registries or epidemiological studies is allowed. In 
case of donor lymphocyte infusions following allogeneic haematopoietic stem cell transplantation or 
biologic agents with a long half-life such as CART cells, immune checkpoint inhibitors, bispecific 
antibodies, a washout of 28 days is allowed. 
11. Patients already enrolled (informed consent signed) and treated in the study 
Inclusion criteria 
General criteria 
12. ECOG performance status ≤ 2 (Appendix 3) 
13. Women of childbearing potential (WOCBP) must use a highly effective method of birth control 
(described in section 5.5), during study and up to 6 months after the last IMP administration. In case of 
use of oral contraception, women should have been stable on the same contraceptive drug (i.e. same 
active principle) for at least one month prior to the first IMP administration 
14. Men with WOCBP partners must use a condom during the study and up to 3 months after the last IMP 
administration. In addition, contraception should be considered for their female partners. Contraceptive 
measures do not apply if the patient is sterile, vasectomized or sexually abstinent. Sperm donation will 
not be allowed during the study and up to 3 months after the last IMP administration. 
Medical and therapeutic criteria 
15. Adequate haematological function based on the last assessment performed within 7 days prior to the 
first IMP administration, defined as: 
- 
Circulating white blood cell count < 10 G/L (only use of hydroxycarbamide or leukapheresis 
before first IMP administration is allowed to achieve this inclusion criterion) 
16. a. Adequate renal function based on the last assessment within 7 days prior to the first IMP 
administration defined as calculated creatinine clearance > 60 mL/min/1.73m², determined by MDRD 
(Appendix 4) 
17. Adequate hepatic function based on the last assessment within 7 days prior to the first IMP 
administration defined as: 
- AST and ALT < 1.5 x ULN and 
- Total serum bilirubin level < 1.5 x ULN, except for patients with known Gilbert’s syndrome 
(confirmed by the UGT1A1 polymorphism analysis) who are excluded if total bilirubin 
> 3.0 x ULN or direct bilirubin > 1.5 x ULN 
Exclusion criteria 
General criteria 
18. Women of childbearing potential (WOCBP) tested positive in a serum pregnancy test within 7 days 
prior to the first day of IMP administration 
19. Patients who have not recovered from toxicity of previous anticancer therapy, including Grade ≥ 2 
toxicity (except alopecia of any grade) according to the National Cancer Institute Common 
Terminology Criteria for Adverse Event (NCI CTCAE) version 5.0, prior to the first IMP administration 


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I.R.I.S. 
Individual 
Study 
Table 
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Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
Medical and therapeutic criteria 
20. Severe or uncontrolled active acute or chronic infection 
21. Uncontrolled hepatitis B or C infection 
22. Known carriers of HIV antibodies 
23. Known history of significant liver disease 
24. Known active acute or chronic pancreatitis 
25. Known active central nervous system disease 
26. Clinically active severe skin diseases 
27. Major surgery within 4 weeks prior to the first IMP administration or patients who have not recovered 
from side effects of the surgery 
28. History of myocardial infarction (MI), unstable angina pectoris or coronary artery bypass graft (CABG) 
within 6 months prior to first IMP administration 
29. a. Troponin I > ULN or Troponin T > ULN if Troponin I cannot be assessed 
30. Clinically significant cardiac dysfunction (including NYHA class ≥ II heart failure, Left Ventricular 
Ejection Fraction (LVEF) < 50% as assessed by echocardiography (ECHO) or Multi-Gated Acquisition 
(MUGA) scan) 
31. QT prolongation defined as QTc interval (corrected with Fridericia’s formula) > 450 ms for males and 
> 470 ms for females, obtained from triplicate 12-lead ECG 
32. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, 
hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained 
sudden death under 40 years of age 
33. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia, atrial fibrillation), complete left 
bundle branch block, high-grade atrioventricular block (AVB) (e.g. bifascicular block, Mobitz type II 
and third degree AVB) 
34. Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood 
pressure (DBP) > 95 mmHg) 
35. Unresolved CTCAE Grade ≥ 2 diarrhoea or presence of medical condition associated with chronic 
diarrhoea (such as irritable bowel syndrome or inflammatory bowel disease) 
36. Coagulopathy that will increase the risk of bleeding complications according to investigator’s judgment 
(e.g. disseminated intravascular coagulation) 
37. Allogenic stem cell transplant within 3 months before the first IMP administration and/or patients who 
still receive immunosuppressive treatment and/or patients with active Graft-versus-host disease 
38. Any previous anti-leukemic treatment for the studied disease within 2 weeks or at least 5 half-lives 
(whichever is longer) of this treatment prior to the first IMP administration (except for 
hydroxycarbamide). In case of donor lymphocyte infusions following allogeneic haematopoietic stem 
cell transplantation or investigational biologic agent with a long half-live such as CART cells, immune 
checkpoint inhibitors or bispecific antibodies, a wash-out of 28 days is allowed 
39. Any radiotherapy within 2 weeks prior to the first IMP administration (except for palliative 
radiotherapy at localised lesions) 
40. Malignant disease other than that being treated in this study. Exceptions include malignancies that were 
treated curatively, have not recurred within 2 years prior to study entry and not requiring ongoing 
therapy, completely resectable basal cell and squamous cell skin cancers, any malignancy considered 
to be indolent and that has never required therapy and completely resected carcinoma in situ of any type 
41. Any clinically significant medical condition (e.g. organ dysfunction, gastric ulcer) or laboratory 
abnormality likely to jeopardize the patients’ safety or to interfere with the conduct of the study, in the 
investigator’s opinion 
42. History of severe allergic or anaphylactic reactions to azacitidine or history of hypersensibility to 
excipient of S64315 or azacitidine, including egg, soybean, liposomal vehicle excipients or mannitol 
(E421) 


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Name of the sponsor: 
I.R.I.S. 
Individual 
Study 
Table 
Referring to Part of the Dossier 
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Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
43. b. Patients receiving treatment medications listed in section 6.3.1 and that cannot be discontinued at 
least 1 week prior to the first IMP administration (at least 2 weeks for CYP3A4 inducers, see 
section 6.3.1 for details) and during the study period. Patients having received calcineurin inhibitors 
within 4 weeks before the first IMP administration. 
For concomitant medication (prohibited or to be used with caution), refer to section 6.3. 
Investigational Medicinal Products (IMPs) 
Arm A 
S64315 (test drug) and azacitidine administered in combination are both IMPs. 
Dose and treatment schedule 
 
 S64315 lead-in dose period 
The lead-in dose period will last 2 weeks. S64315 LID1 will be administered on D-13 at 25 mg and LID2 on D-
6 at 50 mg. LID1 and LID2 doses will be fixed all along the study. 
 
 Combination treatment period 
A treatment cycle will consist of 28 days for patients treated with S64315 in combination with azacitidine during 
the dose escalation phase I part: 
­ Weekly schedule for S64315 on CxD2, CxD9, CxD16 and CxD23 
­ Daily schedule for azacitidine from CxD1 to CxD7 followed by a 21-day rest period 
S64315 will be administered via intravenous (IV) infusion over at least 2 hours. 
The dose escalation will only concern S64315 during the combination treatment period. The starting dose will 
be 50 mg once weekly and doses up to 250 mg may be explored. For more details, see Table (4.1.3.3) 1. 
Azacitidine will be administered at 75 mg/m² via subcutaneous (SC) injection, daily for 7 days from D1 to D7 
of each cycle followed by a rest period of 21 days. 
On days of concomitant administration of S64315 and azacitidine (CxD2), azacitidine should be administered 
2h (±10 minutes (min)) prior to S64315. 
For each cohort, if a dose/treatment combination schedule has not been tested yet, a one-week safety window 
should be observed between C1D2 of the first patient and C1D2 of subsequent patients in the same cohort. If no 
medically important or life-threatening toxicity occurs during the one-week observation period, the subsequent 
patients will be allowed to start treatment without further delays between subsequent patients. 
Depending on the risk of the potential drug-drug interaction (DDI) between the IMPs or emergent safety issues, 
the dose of either or both IMPs may be modified. 
Alternative dosing schedules may be further explored based on the observed clinical safety data, PK/PD data 
and non-clinical data (in vitro, in vivo, PK/PD modelling data). 
In the expansion phase II part, patients will be treated at the RP2D (MTD or suitable lower dose) of S64315 in 
combination with azacitidine identified during the dose escalation phase I part. 
Arm B 
are the IMPs. 
Dose and treatment schedule 
The dose and administrative schedule should be detailed via an amendment 
 
 
Prophylaxis, IMP administration/readministration criteria in Arm A phase I/II are defined hereafter. They 
will be further defined for Arm B via an amendment. 


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Name of the sponsor: 
I.R.I.S. 
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
Anti-emetic prophylaxis 
Anti-emetic prophylaxis is strongly recommended prior to S64315 infusion and azacitidine administration to 
mitigate the risk of gastro-intestinal side effects. For more details, see section 8.2.8.1. 
Tumour Lysis Syndrome (TLS) prophylaxis 
TLS prophylaxis is required during each administration of IMPs for patients with active disease, in case of intra-
patient dose escalation to a new assigned dose and in case of readministration after IMP interruption ≥ 28 days. 
TLS preventive strategies will start the day before the first S64315 infusion of the LID period. In addition to the 
recommendations described in the protocol, management of TLS will be based on international guidelines and 
published criteria (Cairo, 2010). For more details see section 8.2.9. 
Infusion related reaction (IRR) prophylaxis 
IRR prophylaxis is proposed prior to S64315 infusions. For more details, see section 8.2.10. 
IMP administration/readministration criteria 
Criteria to fulfil before each S64315 administration 
­ Before each S64315 infusion, all biological parameters should be checked in order to detect any toxicity (see 
Table (4.1.3.5) 1 and Table (8.12) 1). 
­ Patients with Grade ≥ 2 hypo/hypercalcemia and/or hypo/hypermagnesia and/or hypo/hyperkalaemia despite 
attempts at medical correction should not be treated with S64315 
­ Patients with white blood cell (WBC) count ≥ 10 G/L despite attempts at medical correction should not be 
treated with S64315. Hydroxycarbamide or leukapheresis may be used to reduce the circulating blast count 
before and throughout the study. WBC count must be checked twice a week during the LID period in order 
to maintain the WBC < 10 G/L 
­ AST and ALT ≤ 3 x ULN (except for LID1: AST and ALT ≤ 1.5 x ULN) 
­ Total bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert’s syndrome, who are excluded if 
total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
­ In the case of an S64315 interruption ≥ 28 days, its readministration must be preceded by a lead-in dose 
period (except for patients in CR/CRi). For more details, see section 6.1.2. 
Criteria to fulfil before each first azacitidine administration (i.e. CXD1) 
Patients should be monitored for haematological toxicity and renal toxicities. A delay in starting the next cycle 
or a dose adjustment due to haematological toxicity and/or renal toxicity may be necessary according to 
azacitidine E.U. SmPC (see Table (8.12) 2). WBC, absolute neutrophil count (ANC), platelets, serum creatinine, 
blood urea nitrogen (BUN) and serum bicarbonate will be assessed before starting the next treatment cycle. 
Comparator: Not applicable 
Duration of treatment 
The planned duration of combination treatment is until disease progression, unacceptable toxicity, treatment 
failure or patient/physician decision. 
­ In case the patient becomes eligible for transplant, patient treatment discontinuation should be left to the 
investigator’s decision 
­ In case of myelosuppression within the context of non-active AML, a 4-week interruption of administration 
of one or both IMP(s) will be allowed for bone marrow recovery at the investigator’s discretion after 
discussion and approval from the Sponsor 


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I.R.I.S. 
Individual 
Study 
Table 
Referring to Part of the Dossier 
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Not applicable 
Volume: 
 
Name of Active Ingredient: 
S64315 (also named MIK665) 
Azacitidine 
Page: 
 
If one drug is permanently discontinued, both drugs should be discontinued. A patient should be withdrawn from 
the study if one of the IMPs is interrupted for more than 28 consecutive days for any reason. However, for 
patients with LVEF decline, IMP interruptions of up to 35 consecutive days are permitted. 
If the patient is benefiting from the study treatment according to the investigator’s judgement and if it is in the 
patient’s best interest to continue the combination of S64315 with azacitidine, the patient may remain on study 
treatment. 
A patient must discontinue the combination if the toxicity recurs with the same or worse severity after resumption 
of dosing, unless the investigator decides it is in the patient’s best interest to continue the combination of IMPs 
and upon documented agreement with the Sponsor. 
For each patient, once a dose reduction has occurred, the dose may not be re-escalated during the subsequent 
cycles unless in the opinion of the investigator it is in the patient’s best interest to continue S64315, and upon 
documented agreement with the Sponsor. 
Criteria for treatment discontinuation during the LID period: 
­ If the patient cannot receive the LID2 or the first S64315 C1D2 dose due to an AE, the S64315 infusion 
(either LID2 or C1D2) may be postponed by 1 to 5 days. If the LID2 is postponed for more than 2 days 
(5 days maximum), the C1D2 dose may not be postponed for more than 2 days. If S64315 C1D2 is postponed, 
azacitidine C1D1 dose should be postponed as well, whenever possible. 
­ If the AE is not recovered within this time period, the patient must be withdrawn from the study. 
This study may be temporarily halted or prematurely discontinued at any time for any sufficiently reasonable 
cause. Stopping rules are described in corresponding sections 4.4.1, 4.4.2, 8.12, 10.2.8 and 10.3. 
The end of trial is defined as the date of the last follow-up visit of the last patient, including a phone contact, or 
the date of the last contact attempt if the last patient is declared lost to follow-up. 
Criteria for evaluation 
 
Evaluation criteria in the dose escalation phase I part of Arm A are defined hereafter. They will be updated 
for the expansion phase II part for sub-arms A1 and A2 according to results observed in the phase I part and 
for the dose escalation of Arm B according to the results of Arm A via an amendment. 
Efficacy measurements 
­ All patients will be evaluated for response based on the ‘Diagnosis and management of AML in adults: 2017 
ELN recommendations from an international expert panel (Döhner, 2017) (see Appendix 5). 
­ A full blood count and a blood film examination, a bone marrow aspirate (BMA) and/or a bone marrow 
biopsy (BMB) (according to local medical practice) will be assessed for treatment response at defined time 
points. 
For more details see section 7. 
Safety assessments 
Safety assessments will include: 
­ Incidence of DLTs  
­ Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0 
­ Recording of any change or addition of a new concomitant treatment 
­ Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood coagulation, 
urinary analysis, hepatitis markers, TLS monitoring, cardiac markers follow up 
­ Complete physical examination, ECOG performance status, vital signs measurements 






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Table of contents 
VERSION LIST ......................................................................................................................... 2 
SYNOPSIS ................................................................................................................................. 6 
Contractual signatories ............................................................................................................ 16 
Table of contents ...................................................................................................................... 17 
List of tables ............................................................................................................................. 23 
List of figures ........................................................................................................................... 24 
List of appendices ..................................................................................................................... 25 
List of abbreviations ................................................................................................................. 26 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 31 
2. BACKGROUND INFORMATION ................................................................................. 31 
2.1. Acute myeloid leukaemia ............................................................................................... 31 
2.2. Overview of S64315 (Mcl-1 inhibitor) ........................................................................... 33 
2.2.1. Non clinical data ........................................................................................................... 33 
2.2.2. Clinical data .................................................................................................................. 34 
2.3. Overview of the combination of a Mcl-1 inhibitor and a hypomethylating agent.......... 36 
2.3.1. Rationale of the combination of a Mcl-1 inhibitor and a hypomethylating agent ........ 36 
2.3.2. Non clinical data ........................................................................................................... 36 
2.3.3. Azacitidine clinical data ............................................................................................... 38 
2.3.4. Expected overlapping toxicities ................................................................................... 38 
2.3.5. Pharmacokinetics and metabolism ............................................................................... 39 
2.3.6. Starting dose rationale & administration schedule ....................................................... 39 
2.3.7. Expansion phase II part design rationale ...................................................................... 40 
2.4. Overview of the combination of azacitidine, S64315 and a Bcl-2 inhibitor .................. 40 
2.4.1. Rationale for combination of azacitidine plus Bcl-2 inhibitor ..................................... 40 
2.4.2. Rationale for the combination of a Mcl-1 inhibitor and a Bcl-2 inhibitor ................... 41 
2.4.3. 
... 42 
3. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 43 
3.1. Primary objective ............................................................................................................ 43 
3.2. Secondary objectives ...................................................................................................... 43 
3.3. Exploratory objectives .................................................................................................... 43 
3.4. Endpoints ........................................................................................................................ 43 
4. STUDY DESIGN ............................................................................................................... 46 
4.1. Investigational Plan ......................................................................................................... 46 
4.1.1. Study plan ..................................................................................................................... 46 
4.1.2. Investigation schedule .................................................................................................. 50 
4.1.3. Dose escalation phase I part procedure for Arm A ...................................................... 57 
4.1.3.1. 
General points .......................................................................................................... 57 
4.1.3.2. 
Dose administration schedules................................................................................. 57 
4.1.3.3. 
Dose escalation scheme ........................................................................................... 58 
4.1.3.4. 
Intra-patient dose escalation .................................................................................... 58 
4.1.3.5. 
DLT definition ......................................................................................................... 59 


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4.1.3.6. 
DLT management .................................................................................................... 61 
4.1.3.7. 
Decision process and decision rules ........................................................................ 61 
4.1.4. Expansion phase II part for sub-arms A1 and A2 ........................................................ 61 
4.2. Measures to minimise bias .............................................................................................. 62 
4.3. Study products and blinding systems .............................................................................. 63 
4.3.1. Products administered .................................................................................................. 63 
4.3.2. IMP management .......................................................................................................... 64 
4.3.3. Management of blinding systems ................................................................................. 65 
4.4. Discontinuation of the study ........................................................................................... 66 
4.4.1. Premature discontinuation of the study or temporary halt ........................................... 66 
4.4.2. Criteria for stopping or pausing the study .................................................................... 66 
4.4.3. Discontinuation of the study in the event of objective reached .................................... 66 
4.5. Source data ...................................................................................................................... 66 
5. SELECTION AND WITHDRAWAL OF PATIENTS .................................................. 67 
5.1. Screening criteria ............................................................................................................ 67 
5.1.1. Demographic characteristics ........................................................................................ 67 
5.1.2. Medical and therapeutic criteria ................................................................................... 67 
5.1.3. Informed consent .......................................................................................................... 67 
5.2. Non-screening criteria ..................................................................................................... 67 
5.2.1. Medical and therapeutic criteria ................................................................................... 67 
5.2.2. General criteria ............................................................................................................. 67 
5.3. Inclusion criteria ............................................................................................................. 68 
5.3.1. General criteria ............................................................................................................. 68 
5.3.2. Medical and therapeutic criteria ................................................................................... 68 
5.4. Exclusion criteria ............................................................................................................ 68 
5.4.1. General criteria ............................................................................................................. 68 
5.4.2. Medical and therapeutic criteria ................................................................................... 68 
5.5. Definition of women of childbearing potential and contraception methods................... 70 
5.6. Retest management during screening period .................................................................. 70 
5.7. Additional information recorded at the inclusion visit ................................................... 70 
5.8. Patient withdrawal .......................................................................................................... 70 
5.8.1. Withdrawal criteria ....................................................................................................... 70 
5.8.2. Procedure ...................................................................................................................... 71 
5.8.3. Lost to follow-up .......................................................................................................... 72 
6. TREATMENT OF PATIENTS ........................................................................................ 72 
6.1. IMPs administered .......................................................................................................... 72 
6.1.1. IMP administration schedule ........................................................................................ 72 
6.1.2. Administration/re-administration criteria ..................................................................... 73 
6.2. IMP dispensing ............................................................................................................... 73 
6.3. Previous and concomitant treatments ............................................................................. 73 
6.3.1. List of prohibited medications during the IMP treatment period ................................. 74 
6.3.2. List of medications to be used with caution during the IMP treatment period ............ 74 
6.3.3. List of permitted concomitant medications .................................................................. 75 
6.4. IMP compliance .............................................................................................................. 75 
6.5. IMP discontinuation ........................................................................................................ 75 


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7. ASSESSMENT OF EFFICACY....................................................................................... 76 
7.1. Efficacy measurements ................................................................................................... 76 
7.2. Methods and measurement times .................................................................................... 76 
8. ASSESSMENT OF SAFETY ........................................................................................... 76 
8.1. Specification of safety parameters .................................................................................. 77 
8.2. Methods and measurement times .................................................................................... 77 
8.2.1. Screening period and inclusion visit ............................................................................. 80 
8.2.2. During the treatment period .......................................................................................... 80 
8.2.3. Withdrawal visit ........................................................................................................... 83 
8.2.4. Post-withdrawal follow-up ........................................................................................... 83 
8.2.5. Cardiac safety ............................................................................................................... 83 
8.2.5.1. 
Central ECG recording ............................................................................................ 83 
8.2.5.2. 
Echocardiography/ MUGA scan .............................................................................. 84 
8.2.5.3. 
Cardiac marker follow-up ........................................................................................ 85 
8.2.5.4. 
MRI assessment ....................................................................................................... 85 
8.2.5.5. 
24-hour Holter assessment ....................................................................................... 85 
8.2.6. Hepatic safety ............................................................................................................... 85 
8.2.7. Monitoring of infections that may occur with neutropenia .......................................... 86 
8.2.8. Gastrointestinal disorders ............................................................................................. 86 
8.2.8.1. 
Nausea and vomiting management .......................................................................... 86 
8.2.8.2. 
Diarrhoea management ............................................................................................ 87 
8.2.9. Tumour Lysis Syndrome management ......................................................................... 87 
8.2.10. Infusion Related Reaction management ....................................................................... 89 
8.2.11. Specific COVID-19 situation ....................................................................................... 90 
8.3. Definition of adverse events ........................................................................................... 90 
8.4. Definition of Serious adverse events .............................................................................. 91 
8.5. Definition of overdose .................................................................................................... 92 
8.6. Definition of Adverse event of special interest .............................................................. 92 
8.7. Definition of Events requiring an immediate notification (ERIN) ................................. 92 
8.8. Classification of an adverse event (seriousness, severity, causality, expectedness) ....... 92 
8.9. Reporting procedures ...................................................................................................... 93 
8.9.1. Time frame for AE reporting ........................................................................................ 93 
8.9.2. Responsibilities of the investigator .............................................................................. 94 
8.9.2.1. 
Documentation of the event ..................................................................................... 95 
8.9.2.2. 
Follow-up of adverse events .................................................................................... 95 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP by a person around 
the patient) ............................................................................................................... 95 
8.9.2.4. 
Recording methods in the eCRF .............................................................................. 96 
8.9.2.5. 
Procedure for an event requiring an immediate notification ................................... 96 
8.10. Responsibilities of the sponsor ....................................................................................... 97 
8.11. Responsibilities of Data Safety and Monitoring Board .................................................. 97 
8.12. Management of treatment dose adaptations due to toxicities ......................................... 98 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY 
OR SAFETY .................................................................................................................... 106 
9.1. Assessments related to inclusion criteria. ..................................................................... 106 


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9.2. IMPs concentration measurements ............................................................................... 106 
9.2.1. Blood samples ............................................................................................................ 106 
9.2.2. Identification and transfer of samples ........................................................................ 107 
9.3. Pharmacodynamics measurements ............................................................................... 107 
9.3.1. Mandatory assessments .............................................................................................. 109 
9.3.1.1. 
Sampling and storage ............................................................................................. 109 
9.3.1.2. 
Labelling and shipments ........................................................................................ 110 
9.3.1.3. 
Biomarker assessments .......................................................................................... 111 
9.3.1.4. 
Transfer of analytical results .................................................................................. 112 
9.3.2. Optional assessments .................................................................................................. 112 
9.3.2.1. 
Sampling and storage ............................................................................................. 112 
9.3.2.2. 
Labelling and shipments ........................................................................................ 112 
9.3.2.3. 
Transfer of analytical results .................................................................................. 112 
9.4. Pharmacogenomics measurements ............................................................................... 113 
9.4.1. Sampling and storage ................................................................................................. 113 
9.4.2. Labelling and shipments ............................................................................................. 113 
9.4.3. Transfer of analytical results ...................................................................................... 114 
10. 
STATISTICS ............................................................................................................... 114 
10.1. Overall consideration .................................................................................................... 114 
10.2. Dose escalation phase I part .......................................................................................... 114 
10.2.1. Dose escalation phase I part considerations ............................................................... 114 
10.2.2. Statistical model ......................................................................................................... 115 
10.2.3. Provisional dose levels ............................................................................................... 116 
10.2.4. Prior specifications ..................................................................................................... 116 
10.2.5. Integration of data from CL1-64315-001 study as co-data ........................................ 117 
10.2.6. Dose proposed by the model ...................................................................................... 117 
10.2.7. Dose allocation process .............................................................................................. 118 
10.2.8. Final recommendation and stopping rules .................................................................. 119 
10.3. Expansion phase II part ................................................................................................. 120 
10.3.1. Expansion design ........................................................................................................ 120 
10.3.2. Criteria to re-evaluate the RP2D during the expansion phase .................................... 120 
10.4. Statistical analysis ......................................................................................................... 121 
10.4.1. Evaluation criteria ...................................................................................................... 121 
10.4.1.1. Safety criteria ......................................................................................................... 121 
10.4.1.1.1. Dose escalation phase I part ................................................................................ 121 
10.4.1.1.2. Expansion phase II part ....................................................................................... 121 
10.4.1.2. Activity criteria ...................................................................................................... 122 
10.4.1.2.1. Dose escalation phase I part ................................................................................ 122 
10.4.1.2.2. Expansion phase II part ....................................................................................... 122 
10.4.2. Statistical elements ..................................................................................................... 123 
10.4.3. Analysis sets ............................................................................................................... 123 
10.4.3.1. Dose escalation phase I part ................................................................................... 123 
10.4.3.2. Expansion phase II part.......................................................................................... 123 
10.4.4. Statistical methodology .............................................................................................. 123 
10.4.4.1. Study outcome ....................................................................................................... 123 
10.4.4.2. Safety ..................................................................................................................... 124 
10.4.4.3. Activity .................................................................................................................. 124 
10.4.4.3.1. Dose escalation phase I part ................................................................................ 125 


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10.4.4.3.2. Expansion phase II part ....................................................................................... 125 
10.4.4.4. Biomarkers ............................................................................................................. 125 
10.5. Determination of sample size........................................................................................ 125 
10.5.1. Dose escalation phase I part ....................................................................................... 125 
10.5.2. Expansion phase II part .............................................................................................. 126 
10.6. Pharmacokinetic analyses and PK/PD analysis ............................................................ 126 
10.6.1. Pharmacokinetic interpretation ................................................................................... 126 
10.6.2. PK/PD interpretation when applicable ....................................................................... 127 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................... 127 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 127 
12.1. Study monitoring .......................................................................................................... 127 
12.1.1. Before the study .......................................................................................................... 128 
12.1.2. During the study ......................................................................................................... 128 
12.2. Computerised medical file ............................................................................................ 128 
12.3. Audit - Inspection ......................................................................................................... 129 
12.4. Supervisory committees ................................................................................................ 130 
13. 
ETHICS ....................................................................................................................... 130 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) ................................ 130 
13.2. Study conduct ............................................................................................................... 130 
13.3. Participant information and informed consent .............................................................. 131 
13.4. Modification of the information and consent form ....................................................... 131 
14. 
DATA HANDLING AND RECORD KEEPING ..................................................... 131 
14.1. Study data ..................................................................................................................... 131 
14.2. Data management ......................................................................................................... 132 
14.3. Archiving ...................................................................................................................... 133 
15. 
INSURANCE ............................................................................................................... 133 
16. 
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY .............................................................................................. 133 
17. 
ADMINISTRATIVE CLAUSES ............................................................................... 134 
17.1. Concerning the sponsor and the investigator ................................................................ 134 
17.1.1. Persons to inform ........................................................................................................ 134 
17.1.2. Substantial protocol amendment and amended protocol ............................................ 134 
17.1.3. Final study report ........................................................................................................ 135 
17.2. Concerning the sponsor ................................................................................................ 135 
17.3. Concerning the investigator .......................................................................................... 136 
17.3.1. Confidentiality - Use of information .......................................................................... 136 
17.3.2. Organisation of the centre .......................................................................................... 136 
17.3.3. Documentation supplied to the sponsor ..................................................................... 137 
18. 
REFERENCES ............................................................................................................ 137 


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19. 
APPENDICES ............................................................................................................. 142 
 


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List of tables 
Table (2.3.2) 1 - Synergistic interactions of S63845 and decitabine were assessed using 
the Loewe additivity model to derive Synergy Score (SS), with SS > 3 indicating 
synergy and SS > 5 strong synergy .......................................................................................... 36 
Table (3.4) 1 - Endpoints for dose escalation phase I part – Arm A ........................................ 43 
Table (3.4) 2 - Endpoints for expansion phase II part – sub-arms A1 and A2......................... 44 
Table (3.4) 3 - Endpoints for dose escalation phase I part – Arm B ........................................ 45 
Table (4.1.2) 1 - Investigation schedule for arm A .................................................................. 51 
Table (4.1.2) 2 - Pharmacokinetic measurements for arm A ................................................... 56 
Table (4.1.3.3) 1 - Provisional dose levels of S64315 ............................................................. 58 
Table (4.1.3.5) 1 - Toxicity criteria according to NCI CTCAE grading .................................. 59 
Table (4.1.3.5) 2 - Non evaluability criteria ............................................................................. 60 
Table (4.1.3.5) 3 - Minimum number of S64315 and azacitidine doses to meet minimum 
exposure until the end of cycle 1 .............................................................................................. 61 
Table (4.3.1) 1 - Description of the IMPs (S64315 and azacitidine) ....................................... 63 
Table (4.3.1) 2 - Description of packaging .............................................................................. 64 
Table (8) 1 - Mitigation strategies of the identified risks ......................................................... 77 
Table (8.2) 1 - Local Clinical laboratory parameters collection plan ...................................... 78 
Table (8.2) 2 - Central ECGs collection plan ........................................................................... 79 
Table (8.2.5.1) 1 - Toxicity grading of QTc interval prolongation is defined by the 
CTCAE (v 5.0) ......................................................................................................................... 84 
Table (8.2.8.1) 1 - Treatments schedule for nausea/vomiting prophylaxis .............................. 87 
Table (8.12) 1 - Criteria for interruption and re-initiation of S64315 ...................................... 99 
Table (8.12) 2 - Criteria for interruption and re-initiation of azacitidine (see E.U. 
azacitidine SmPC) .................................................................................................................. 105 
Table (9.2.1) 1 - Time points for drug concentration assessment during dose escalation 
phase I part ............................................................................................................................. 106 
Table (9.3) 1 - Biomarker sample collection plan .................................................................. 108 
Table (10.2.3) 1 - Provisional dose levels .............................................................................. 116 
 


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List of figures 
Figure (2.3.2) 1 - Ex vivo activity of S63845 in combination with azacitidine in primary 
 37 
Figure (2.3.2) 2 - Combined S63845 and decitabine suppress leukaemia in vivo in 
NRG-SG3 patient-derived xenograft models of AML (Moujalled, 2019) ............................... 37 
Figure (2.4.2) 1 - Combined targeting of BCL-2 and MCL-1 improves the survival of 
mice  xenografted with human AML ....................................................................................... 41 
Figure (4.1.1) 1 - Study plan for S64315 administration schedule in combination with 
azacitidine (dose escalation phase I part – Arm A) .................................................................. 48 
Figure (4.1.1) 2 - Overall study plan ........................................................................................ 49 
Figure (8.2.10) 1 - Management of IRR to systemic anticancer therapy ESMO clinical 
practice guidelines .................................................................................................................... 90 
Figure (10.2.7) 1 - Dose-allocation process ........................................................................... 119 
 


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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki ........................................ 142 
Appendix 2: Patient Registration Form .................................................................................. 148 
Appendix 3: Patient performance status ................................................................................. 149 
Appendix 4: MDRD formula (Levey et al, 2006) .................................................................. 150 
Appendix 5: Response criteria in acute myeloid leukemia according to Diagnosis and 
Management of AML in Adults: 2017 ELN Recommendations from an International 
Expert Panel ........................................................................................................................... 151 
Appendix 6: Dose allocation meeting minutes template ........................................................ 153 
Appendix 7: Guidance for diarrhoea management (ESMO, 2018) ........................................ 154 
Appendix 8: Statistical aspects for the dose escalation phase I part and the expansion 
phase II part with an interim analysis for futility ................................................................... 155 
Appendix 9: Local modification of the clinical study protocol ............................................. 171 
Appendix 10: Instructions to investigator for handling data rights requests .......................... 172 
 


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List of abbreviations 
% 
: percent 
µmol 
: micromole 
ADL 
: Activities of Daily Living 
ADME 
: Absorption Distribution Metabolism Excretion 
AE 
: Adverse Event 
ALP 
: ALkaline Phosphatase 
ALT 
: ALanine aminoTransferase 
AML 
: Acute Myeloid Leukaemia 
ANC 
: Absolute Neutrophil Count 
APL 
: Acute Promyelocytic Leukaemia 
aPTT 
: activated Partial Thromboplastin Time 
AST 
: ASpartate aminoTransferase 
AUC 
: Area Under the Curve 
AUC24 
: Area Under the Curve at 24 hours 
AUClast 
: Area under the concentration-time curve from time zero to time o
last measurable concentration 
AUCτ 
: Area under the plasma concentration-time curve 
AVB 
: AtrioVentricular Block 
AZA 
: Azacitidine 
ß hCG 
: ß Human Chorionic Gonadotrophin 
BCL2 
: B-cell lymphoma 2 gene 
Bcl-2 
: B-cell lymphoma 2 protein 
BH3 
: Bcl-2 Homology domain 3 
BLRM 
: Bayesian Logistic Regression Model 
BMA 
: Bone Marrow Aspirate 
BMB 
: Bone Marrow Biopsy 
BMMC 
: Bone Marrow-derived Mononuclear Cells 
BMI 
: Body Mass Index 
BNP 
: Brain Natriuric Peptide 
BP 
: Blood Pressure 
BR 
: Best Response 
bpm 
: beats per minute (heart rate unit) 
BSA 
: Body Surface Area 
BNP 
: Brain Natriuretic Peptide 
BUN 
: Blood Urea Nitrogen 
C 
: Cycle 
CABG 
: Coronary Artery Bypass Graft 
CAD 
: Coronary Artery Disease 
CI 
: Confidence Interval 
Cinf 
: Concentration at the end of infusion 
CISO 
: Chief information security officer 
CK 
: Creatine Kinase 
CL 
: total CLearance 
Clast 
: Last quantifiable observed concentration 
CLL 
: Chronic Lymphocytic Leukaemia 
cm 
: Centimetre 
Cmax 
: maximum Concentration 


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Cmin 
: minimum Concentration 
CMP 
: Clinical Monitoring Plan 
CNS 
: Central Nervous System 
CPK 
: Creatine Phosphokinase 
CPK-MB 
: Creatine PhosphoKinase Myocardial Band 
CR 
: Complete Remission 
CRA 
: Clinical Research Associate 
CRi 
: Complete Remission with incomplete haematologic recovery 
CRMRD- 
: Complete Remission without Minimal Residual Disease 
CRO 
: Contract Research Organisation 
CSR 
: Clinical Study Report 
CTCAE 
: Common Terminology Criteria for Adverse Events 
CT 
: Computed Tomography 
CV 
: Curriculum Vitae 
CXR 
: Chest X-Ray 
D 
: Day 
DBP 
: Diastolic Blood Pressure 
DDI 
: Drug-Drug Interaction 
DFS 
: Disease-Free Survival 
DLT 
: Dose Limiting Toxicity 
DLTES 
: Dose-Limiting Toxicity Evaluable Set 
DSMB 
: Data Safety and Monitoring Board 
DOR 
: Duration Of Response 
DPO 
: Data Protection Officer 
e.g. 
: Exempli gratia (for example) 
ECG 
: ElectroCardioGram 
ECHO 
: Echocardiogram 
EAE 
: Emergent Adverse Event 
eCRF 
: Electronic Case Report Form 
ECOG 
: Eastern Cooperative Oncology Group 
EMA 
: European Medicines Agency 
EoC 
: End of Cohort 
EoI 
: End of Infusion 
ERIN 
: Event Requiring Immediate Notification 
EWOC 
: Escalation With Overdose Control 
FAS 
: Full Analysis Set 
FDA 
: Food and Drug Administration 
FFPE 
: Formalin-Fixed Paraffin-Embedded 
FU 
: Follow-Up 
FVFP 
: First Visit First Patient 
g 
: Gram 
G/L 
: Giga (109) per litre 
GCP 
: Good Clinical Practice 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl 
Transpeptidase) 
GI 
: GastroIntestinal 
GLP 
: Good Laboratory Practice 
GLS 
: Global Longitudinal Strain 
GMP 
: Good Manufacturing Practice 
GVHD 
: Graft-versus-host disease  


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h 
: Hour 
HBs 
: Surface antigen of Hepatitis B virus 
hERG 
: Ether-à-go-go-Related Gene 
HIV 
: Human Immunodeficiency Virus 
HMA 
: HypoMethylating Agents 
HNSTD 
: Highest Non Severely Toxic Dose 
HPLC 
: High-Performance Liquid Chromatography 
HR 
: Heart Rate 
HSCT 
: Haematopoietic Stem Cell Transplant 
IB 
: Investigator’s Brochure 
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 
IMP 
: Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial i.e. S64315 and azacitidine 
INR 
: International Normalized Ratio 
IRB 
: Institutional Review Board 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
IRR 
: Infusion Related Reaction 
IS 
: Included Set 
IU 
: International Unit 
IUD 
: IntraUterine (contraceptive) Device 
IUS 
: IntraUterine hormone-releasing System 
IV 
: IntraVenous (route) 
kg 
: Kilogram 
L 
: Litre 
LDH 
: Lactate DeHydrogenase 
LDL 
: Low-Density Lipoprotein 
LFT 
: Liver Function Tests 
LID 
: Lead-In Dose 
LLN 
: Lower Limit of reference range 
LV 
: Liposomal Vehicle 
LVEF 
: Left Ventricular Ejection Fraction 
MCL1 
: HGNC Approved Gene Symbol for Myeloid Cell Leukaemia 
Sequence 1 
Mcl-1 
: Induced myeloid leukaemia cell differentiation protein 
MDRD 
: Modification of Diet in Renal Disease 
MDS 
: MyeloDysplastic Syndrome 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: Milligram 
MI 
: Myocardial Infarction 
min 
: Minute 
mL 
: Millilitre 
mm 
: Millimetre 
mmHg 
: Millimetre of mercury 
mmol 
: Millimole 
msec 
: Millisecond 


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MLFS 
: Morphologic Leukaemia-Free State 
MM 
: Multiple Myeloma 
MRD 
: Minimal (measurable) Residual Disease 
MS/MS 
: tandem Mass Spectrometry 
MTD 
: Maximum Tolerated Dose 
MUGA scan 
: Multi-Gated Acquisition scan 
NA 
: Not Applicable 
NAE 
: Number of Adverse Events 
NCA 
: Non-Compartmental Analysis 
NCI 
: National Cancer Institute 
NCT 
: EudraCT Number 
NGS 
: Next Generation Sequencing 
ng 
: Nanogram 
NTI 
: Narrow Therapeutic Index 
NS 
: Not statistically Significant 
NYHA 
: New York Heart Association 
OPM 
: OPerating Manual 
ORR 
: Overall Response Rate 
OS 
: Overall Survival 
p.o. 
: per os (orally) 
PBMC 
: Peripheral Blood-derived Mononuclear Cells 
PBPK 
: Physiologically-based PharmacoKinetic 
PD 
: PharmacoDynamics 
PDX 
: Patient-Derived Xenograft 
PFS 
: Progression Free Survival 
PG 
: PharmacoGenomics 
P-GP 
: P-glycoprotein 1 
Ph. Eur. 
: European Pharmacopeia 
PK 
: PharmacoKinetics 
PR 
: Partial response  
po 
: per os (orally) 
PPS 
: Per Protocol Set 
PS 
: Performance Status 
QC 
: Quality Control 
QD 
: Once daily 
QTc 
: QT interval corrected for heart rate 
QTcF 
: QTc interval corrected with Fridericia’s formula 
RBC 
: Red Blood Cells 
RNA 
: Ribonucleic acid 
RP2D 
: Recommended Phase II Dose 
SAE 
: Serious Adverse Event 
SBP 
: Systolic Blood Pressure 
SC 
: SubCutaneous (route) 
SD 
: Standard Deviation 
SLL 
: Small Lymphocytic Lymphoma 
SE 
: Standard Error 
sec 
: Second 
SmPC 
: Summary of Product Characteristics 
SoI 
: Start of Infusion 
SS 
: Safety Set 


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SUSAR 
: Suspected Unexpected Serious Adverse Reaction 
T 
: Temperature 
t½z 
: terminal half-life 
TdP 
: Torsades de Pointes 
test drug 
: Drug substance in a given dosage form, tested in a clinical trial, 
i.e. S64315  
tlast 
: Time corresponding to Clast 
TLS 
: Tumour Lysis Syndrome 
tmax 
: Time corresponding to Cmax 
TPN 
: Total parenteral nutrition 
TSH 
: Thyroid Stimulating Hormone 
TTE 
: TransThoracic Echocardiography 
TU 
: Therapeutic Unit 
ULN 
: Upper Limit of reference range 
USP-NF 
: United States Pharmacopeia and The National Formulary 
Vd 
: Volume of distribution 
WBC 
: White Blood Cells 
WHO 
: World Health Organization 
WHO-DD 
: World Health Organization, Drug Dictionary 
WMA 
: World Medical Association 
WOCBP 
: Woman of Child Bearing Potential 
WV 
: Withdrawal Visit 
 
 
 


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1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Non sponsor parties, sponsors 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 for each country is given in separate documents attached to the protocol 
and entitled ‘Investigators list for [name of the country]’. 
The composition and role of the supervisory committee are described in sections 8.11 and 12.4. 
2. BACKGROUND INFORMATION 
2.1. Acute myeloid leukaemia 
Acute myeloid leukaemia (AML) is the result of a multistep transforming process of 
hematopoietic precursor cells, which enables them to proceed through limitless numbers of cell 
cycles and to become resistant to cell death. Increased proliferation renders these cells 
vulnerable to acquiring mutations and may favour leukemic evolution. Deregulated cell cycle 
control contributes to increased proliferation in AML and favours genomic instability, a 
prerequisite to confer selective advantages to particular clones in order to adapt and 
independently proliferate in the presence of a changing microenvironment (Schnerch, 2012). A 
number of chromosomal and molecular genetic abnormalities has been described in this disease. 
Sub-classification based on these abnormalities guides prognosis (Döhner, 2017). 
The yearly incidence of AML in European adults is 5-8 cases per 100 000 (Fey, 2013), 4.2 cases 
per 100,000 in US (Society AC. Cancer Facts & Figures, 2016) and 3.9 cases per 100,000 
people in Australia (Australian Institute of Health and Welfare, 2012). Outcome for patients are 
poor with a 5-year survival rate of 26.9%. Untreated patients succumb to AML within weeks 
(Institute NC. Cancer Stat Facts: AML, 2017; Maldonado, 2015). 
The incidence of AML increases approximately by 10-fold with age, from 1.3 cases per 100,000 
people under 65 years of age to 12.2 cases per 100,000 in those over 65 years of age (De 
Kouchkowsky, 2016). AML is the most common acute leukaemia in the adult population, and 
largely affects older patients, with a median age at diagnosis of 68 years. Approximately 1/3 of 
all new diagnoses are aged 75 years and over (Institute NC. SEER Stat Facts Sheets: AML, 
2016). In the elderly population, outcome is dismal with less than 5% survival at 5-years 
compared to a rate of 40% in younger patients (Alibhai, 2009). Long-term survival rate remains 
low with a median overall survival estimated at 7.0 months (Meyers, 2013). This is driven by 
the aggressive clinico-pathologic features of AML compounded with the comorbidities and 
frailty of this population. 
The standard initial management for fitter patients with minimal comorbidities is intensive 
chemotherapy; older, less fit patients tolerate this poorly, resulting in limited effective treatment 
options (Cortes, 2019; Kantarjian, 2012). Historically, these patients have been referred for 
palliative or supportive care or treated with single-agent hypomethylating agents (HMAs) or 
low-dose cytarabine (LDAC), which have modest response rates.  


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AML is a biologically complex tumour with high rates of drug resistance. The goal of therapy 
is to reduce tumour burden and to re-establish normal bone marrow function and 
haematopoiesis. Evidence of minimal residual disease (MRD) places the patient at risk of 
relapse and short-term survival (Pettit, 2016). The central tenet of treatment is to cytoreduce 
with induction therapy while allowing the patient to emerge in a condition to tolerate subsequent 
more intensive consolidation therapy, which may include allogeneic haematopoietic stem cell 
transplantation (HSCT). Patients who do not receive consolidation therapy relapse within 
6-9 months. 
Initial treatment decisions are based on age, performance status, prior myelodysplastic 
syndrome and prior cytotoxic therapy. 
Standard induction therapy for patients under the age of 60 usually consists of cytarabine and 
daunorubicin regimen. Overall outcomes for standard induction therapy are disappointing with 
complete response (CR) rate between 60-80% (Murphy, 2017). Half of those who do not reach 
complete remission experience fatal complications related to bone marrow aplasia or impaired 
recovery of normal haematopoiesis and the remaining population develop chemotherapy 
resistant disease. 
Older patients present a particular challenge in the management of AML. In this population, 
AML is characterized by unfavourable karyotypes and higher mutational burden. Furthermore, 
the incidence of secondary AML, related to prior MDS or prior chemotherapy is higher in this 
population where current standard of care regimen may be difficult to tolerate, and treatment-
related mortality may exceed expected anti-leukemic response. 
Allogeneic HSCT, the only realistic hope of cure for these patients, is an option for a minority. 
Only patients with low tumour-burden and a long remission period (response 
rates > 12 months) appear to benefit from this treatment. Despite the curative intent, outcomes 
in these patients are sub-optimal. In a long-term follow-up study of post-allogeneic HSCT in 
AML and MDS patients, the reported relapse rate was 42% at 5 years (Finke, 2016). Besides 
allogeneic HSCT, no curative treatment exists for patients with relapsed AML. This is even 
more challenging in older patients, who usually experience short remissions (< 1 year) and are 
often considered unfit to tolerate intensive treatments (Ferrara, 2004). 
Due to the high rates of relapse or recurrence in AML, there is a great need for effective salvage 
therapies. 
In recent years, much has been learned about the genomic and epigenomic landscapes of AML, 
and the clonal architecture of both de novo and secondary AML has begun to be unravelled. 
Genetic studies in AML have revealed a variety of mutated or overexpressed proteins that, alone 
or in combination, contribute to leukemogenesis. New targeted therapies aimed at inhibiting 
these proteins are in development for treatment of AML. Since the past year, several novel 
agents have been approved by the US Food and Drug Administration (FDA) for use in patients 
with AML. Indeed I, 2017, the FLT3 inhibitor midostaurin, the antibody-drug conjugate 
gemtuzumab ozogamicin, CPX-351 (liposomal daunorubicin and cytarabine), and the IDH2 
inhibitor enasidenib were approved. In 2018, other 4 new compounds were approved: the IDH1 
inhibitor ivosidenib, the FLT3 inhibitor new generation gilteritinib, the first in class Hedghog 
pathway glasdegid, and the Bcl-2 inhibitor venetoclax. The latter received a granted accelerated 
approval in November 2018 in combination with azacitidine, decitabine or low-dose cytarabine 
(LDAC) for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or 
who have comorbidities that preclude use of intensive induction chemotherapy in the frame of 
a phase I/II. 


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This recent U.S. FDA approval of venetoclax with HMAs or LDAC in patients with AML who 
are previously untreated and older or unfit for chemotherapy has resulted in a promising therapy 
for these patients (DiNardo, 2018; Wei, 2019). 
Despite advances in our understanding of the molecular basis for particular subtypes of AML 
and despite four new drugs approved for patients with FLT3 mutant, IDH2 mutant, CD33 
positive AML, t-AML, and AML-MRC (Wei, 2017), a significant proportion of AML patients 
cannot be treated. New therapies are clearly needed, and in particular, there is a need to develop 
targeted therapies that avoid the use of cytotoxic drugs, many of which are also known 
mutagens. 
2.2. Overview of S64315 (Mcl-1 inhibitor) 
S64315 background 
One of the cardinal features of cancer is a dysregulation of apoptosis (Hanahan, 2011) 
(Hanahan, 2011) Apoptosis is a physiological vital process for the maintenance of homeostasis 
in multicellular organisms, but it is also involved in a wide range of pathological processes, 
including cancer.  
The regulation of apoptotic cell death is primarily controlled by the complex interactions of the 
Bcl-2 family of proteins (Kim, 2006; Kale, 2018). The Bcl-2 family comprises both pro (such 
as Bax, Bak, Noxa, PUMA, Bim, and Bid) and anti-apoptotic members, the latter (such as Bcl-
2, Bcl-xL, Bcl-w, Mcl-1 and Bfl-1/A1) are often overexpressed in cancer cells allowing a 
deregulated survival (Adams, 2018). 
Small molecule selective Bcl-2 family inhibitors induce apoptotic cell death by releasing pro-
apoptotic members (Tse, 2008; Danial, 2004; Green, 2004). Pharmacological inhibition of 
antiapoptotic Bcl-2 subfamily members in cancer has emerged as one of the strategies to induce 
apoptosis and cause tumour regression (Zhang, 2007). 
Mcl-1 (induced myeloid leukaemia cell differentiation protein) was the second member of the 
Bcl-2 family discovered (Kozopas, 1993). Mcl-1 is highly expressed in a variety of human 
cancer cell lines, human haematopoietic, lymphoid cancers and solid tumours (Quinn, 2011). 
Mcl-1 overexpression is exploited by cancer cells to evade cell death, i.e. to survive, and as a 
mechanism for developing resistance to diverse chemotherapeutic agents (Akgus, 2009) Mcl-1 
plays a crucial role in cell differentiation, regulation of apoptotic cell death, and has been shown 
to be critical to the development and maintenance of AML, making it an attractive therapeutic 
target in this disease. 
In line with this observation, molecules targeting Mcl-1 such as S64315 (also named MIK665) 
are expected to be active in combination with conventional therapies (Hata, 2005). 
2.2.1. 
Non clinical data 
Pharmacology 
S64315 (MIK665) is an innovative Bcl-2 Homology domain 3 (BH3) mimetic compound which 
selectively inhibits Mcl-1, a prosurvival member of the Bcl-2 family proteins. 
S64315 is a synthetic small molecule which binds selectively to Mcl-1 with a very high affinity 
(IC50 range 3-6 nM in a displacement assay) and with low affinity to Bcl-2 and Bcl-xL. 
In vitro, the ability of S64315 to inhibit cell growth was investigated in a panel of 
haematological cell lines including AML, lymphoma and multiple myeloma human cell lines. 
Most of the cell lines tested was sensitive to S64315, with IC50 below 100 nM. 


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In vivo, S64315 administered IV induced a rapid dose-dependent apoptotic response and tumour 
growth inhibition in an AML xenograft model. These data show that the in vitro potency of 
S64315 against haematological cell lines well translates to potent in vivo activity. For details, 
please refer to S64315 Investigator’s Brochure. 
S64315 was assessed for its off-target activity on receptors, enzymes and ion channels; 
however, the values obtained show that inhibition of the latter is unlikely in a clinical setting. 
Pharmacokinetics and Metabolism 
In preclinical IV studies, S64315 displayed a very high plasma protein binding across species 
(fraction unbound (fu) in plasma < 0.1% in mouse, rat, monkey and human) with more than 
80% of the drug distributed in plasma. There was no concentration-dependency observed for 
rat, monkey and human plasma. 
In a mouse distribution study using non-radiolabelled S64315, high liver exposure was 
observed with low to moderate uptake into muscle and adipose tissue and very low brain 
exposure. 
In vitro, cross-species metabolism studies showed a moderate to high in vitro predicted hepatic 
clearance in mouse, rat, dog, monkey and human. Based on human hepatocyte data, S64315 is 
mainly metabolised through oxidative routes by CYP3A4 (50%) and CYP2C8 (20%). Direct 
glucuronidation of S64315 contributes to S64315 clearance for 30% or less. There is a moderate 
drug-drug interaction (DDI) risk when combining S64315 with CYP3A4 perpetrators and a low 
risk with CYP2C8 perpetrators. 
Based on rat excretion data, renal clearance is predicted to be minor (less than 0.1% of the 
administered dose is excreted as unchanged S64315 within urine). The risk of DDI will have to 
be further investigated in clinic. 
Toxicology 
Preclinical cardiovascular safety pharmacology data do not indicate a risk for QTc prolongation 
or arrhythmogenicity based on the hERG assay, monkey telemetry studies, and ECGs evaluated 
in the 4-week GLP study in monkeys. There were no appreciable effects on CNS function or 
change in seizure threshold nor were there any effects on respiration observed in any study. 
S64315 was devoid of in vitro and in vivo genotoxic potential. 
In addition to the haematotoxicity, the principal target organs of toxicity following repeated 
S64315 administration (whatever the schedule of administration, either once weekly during 
4 weeks or every 2 to 3 days during 2 weeks) to rats and monkeys include: bone marrow 
(depletion, hypocellularity), lymph organs (depletion and atrophy), liver (hepatocellular single-
cell necrosis/apoptosis), gastrointestinal tract (epithelial cell single cell necrosis/apoptosis), 
pancreas (acinar cell single-cell necrosis/apoptosis), heart (increased staining of 
cardiomyocytes for cleaved caspase 3), testes (germ cell depletion), ovary (granulosa cell 
single-cell necrosis/apoptosis), skin (localized degeneration and cutaneous inflammation), eye 
(corneal degeneration and opacity and cataracts). 
All these changes showed recovery after a 4-week dosing period. 
For details, please refer to S64315 Investigator’s Brochure (IB). 
2.2.2. 
Clinical data 
As of September 5th, 2019 (IB cut-off date), three clinical studies were ongoing in patients with 
haematological malignancies. 


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­ Two phase I studies with S64315 as a single agent in patients with: 
 AML and myelodysplastic syndromes (MDS) conducted by Institut de Recherches 
Internationales Servier (CL1-64315-001). Thirty-eight (38) patients have been treated in 
this study with dose ranging 50-500 mg of S64315 as a weekly intravenous infusion. The 
dose of 500 mg was identified to be toxic, cardiotoxicity being the dose-limiting toxicity 
(see IB section ‘Guidance for Investigator 7.11.6. Cardiovascular’) and 300 mg has been 
established as the highest safe dose allowable by the EWOC criterion. No objective 
response was observed across the dose range, even though pharmacodynamics effects 
with bone marrow blast reduction were observed in 10/25 patients. Following the 
assessment of the benefit-risk of S64315 as single agent in AML/MDS patients, i.e. no 
objective response observed whereas toxic dose reached (i.e. 500mg), it was decided to 
definitively discontinue the development of S64315 in monotherapy in AML/MDS 
patients and therefore to discontinue the CL1-64315-001 study. Taking into account the 
mechanism of action, the role of the other BH3 mimetics proteins and the heterogeneity 
of the BCL2 family member’s expression in AML, further development of S64315 in 
combination is considered in AML. 
 Lymphomas and multiple myeloma (MM) conducted by Novartis Pharmaceuticals 
(CMIK665X2101). Thirty-one (31) patients have been treated since the start of the study. 
The benefit-risk assessment of MIK665 as single agent in MM and lymphoma indication 
is currently under evaluation while the study is not recruiting new patients. 
­ One phase Ib study with S64315 in combination with a Bcl-2 inhibitor (venetoclax) in 
patients with AML conducted by Institut de Recherches Internationales Servier (CL1-64315-
002). Twelve (12) patients have been treated since the start of the study. The benefit-risk 
assessment of S64315 in combination with venetoclax in AML patients is still considered 
favourable providing that additional safety measures, especially towards cardiac safety 
monitoring have been implemented. 
The most frequently reported adverse events (AEs) (in ≥ 15% of the patients) irrespective of 
the relationship to the study drug involved the SOC gastrointestinal disorders and the SOC 
investigations. The most frequently reported preferred terms among gastrointestinal disorders 
were nausea, vomiting and diarrhoea and, among investigations, troponin I increased, alanine 
aminotransferase increased, and aspartate aminotransferase (AST/SGOT) increased. The most 
frequent severe AEs independently from the relationship to the study drug were febrile 
neutropenia, anaemia and neutropenia.  
For more details on S64315 global safety, please refer to the last version of the IB (e.g. 
section 7: Guidance for investigator). 
Pharmacokinetic properties 
Preliminary PK data from the single agent studies were analysed by population PK modelling 
and were adequately described by a 3-compartment model with linear clearance estimated to 
15.9 L/h. 
High level interpretation based on the preliminary PK data and population PK modelling shows 
low to moderate variability (~30%) on exposure metrics (Cmax, AUC). Exposure appears to 
increase proportionally with the dose, independently of the time and to be comparable between 
CMIK665X2101 and CL1-64315-001 studies. Exposure is quickly decreasing after end of 
infusion implying that AUC24h is comparable to AUCtau, deviating less than 5%. 




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The combination of S63845 and azacitidine was also tested in ex vivo AML primary patient 
samples Figure (2.3.2) 1. The combination mostly induces synergistic activity, even in samples 
resistant to azacitidine. 
Figure (2.3.2) 1 - Ex vivo activity of S63845 in combination with azacitidine in primary AML samples 
 
 
Ficoll purified AML cells were exposed to drugs over a period of 48 hours. Viability was determined by cellular 
exclusion of SYTOX Blue Dead Cell Stain. Analysis was performed in 34 independent donors and 4 representative 
AML samples were represented. 
Finally, the combination of S63845 and decitabine was tested in in vivo AML patient derived 
xenografts (PDX) as shown in Figure (2.3.2) 2. This combination induces more activity when 
compared to the single agents. 
Figure (2.3.2) 2 - Combined S63845 and decitabine suppress leukaemia in vivo 
in NRG-SG3 patient-derived xenograft models of AML (Moujalled, 2019) 
 
 


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These data suggest that when S63845, tool compound of S64315, and decitabine are 
concomitantly administered, the Mcl-1 inhibitor may enhance the effect of the HMA in 
relapsed/refractory and treatment naive AML patients. This further supports the evaluation of 
the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-leukemic activity of 
S64315 in combination with azacitidine in a clinical study. 
2.3.3. 
Azacitidine clinical data 
Azacitidine is an HMA commonly used in the treatment of AML. It is approved by the FDA 
and EMA. According to E.U SmPC, azacitidine is indicated for the treatment of adult patients 
who are not eligible for HSCT with AML with 20-30 % blasts and multi-lineage dysplasia, 
according to World Health Organisation (WHO) classification and AML with >30% marrow 
blasts according to the WHO classification. 
Myelosuppression is the main dose-limiting toxicity for azacitidine. The risk is higher during 
the first 2 cycles and decreases when the patient’s haematological function is restored. Less 
than 5% of patients required drug discontinuation due to haematological side effects. Close 
monitoring for haematological toxicity is recommended, including nadir counts, and supportive 
care provided when required. Doses for subsequent cycles should be adjusted based on nadir 
counts and haematological response (see E.U. azacitidine SmPC). Myelosuppression may lead 
to neutropenia and an increased risk of infection. Serious adverse reactions such as sepsis, 
including neutropenic sepsis and pneumonia, were reported in patients receiving azacitidine. 
Infections may be managed with the use of anti-infectives plus growth factor support (e.g. G-
CSF) for neutropenia. 
The most common non-haematological side effects are injection site reactions, nausea, 
vomiting, fatigue, and diarrhoea/ constipation. The gastrointestinal adverse reactions are to be 
managed symptomatically with anti-emetics for nausea and vomiting, anti-diarrhoeals for 
diarrhoea, and laxatives and/or stool softeners for constipation. 
Severe hepatic failure has been reported in patients with extensive disease and 
hypoalbuminemia. Therefore, azacitidine is contraindicated in patients with advanced 
malignant hepatic tumours. 
No clinically relevant difference in the frequency of adverse reactions was noted between 
subjects with normal renal function compared to those with renal impairment. Nevertheless, 
patients with renal impairment should be closely monitored for toxicity since azacitidine and/or 
its metabolites are primarily excreted by the kidney, as some rare cases of renal tubular 
dysfunction have been reported. 
2.3.4. 
Expected overlapping toxicities 
Based on preclinical data from both drugs, clinical data from azacitidine as a single agent in 
monotherapy as well as preliminary clinical data available from ongoing studies with S64315, 
bone marrow and lymphoid organs are identified as primary target organs for toxicity; 
overlapping myelosuppression may be observed. The risk of tumour lysis syndrome (TLS) has 
also to be considered. Other overlapping toxicities such as gastrointestinal disorders may be 
observed (see section 8 for toxicity prophylaxis). 
Even if pharmacology investigations indicate the potential for synergistic toxicity, no dedicated 
combination toxicity study had been considered since the safety of azacitidine is well known. 
The measures implemented, including clinical monitoring and described in the section 8 of this 
document are deemed sufficient to mitigate the risk and to predict clinical dose adjustments. 


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2.3.5. 
Pharmacokinetics and metabolism 
When coadministered, in vitro results show an inhibition of hepatic efflux (P-GP) of S64315 
by azacitidine. With limited in vitro/in vivo information for azacitidine, population based 
pharmacokinetic (PBPK) simulations have been performed to quantify this impact. PBPK 
simulations show a very limited DDI risk between azacitidine and S64315 with concomitant 
administration. Thus, from a PK point of view, there is no recommendation of starting dose 
adaptation due to DDI risk.  
2.3.6. 
Starting dose rationale & administration schedule 
In the study CL1-64315-001 assessing S64315 as a single agent in a weekly schedule without 
lead-in dose period, doses from 50 to 500 mg were tested. Based on all the DLT data collected 
since the beginning of the study across 38 evaluable patients with AML or MDS, 500 mg was 
identified to be a toxic dose and 300 mg was the highest dose considered safe by the statistical 
model i.e. BLRM with EWOC criterion. Nevertheless, considering the global safety observed 
at 300 mg (except DLT), it was decided not to overpass S64315 weekly dose of 250 mg. 
 
­ Arm A evaluating the combination of S64315 with azacitidine in the frame of a phase 
I/II trial 
 Dose escalation phase I part 
The choice of the starting dose of S64315 in the Arm A is based on the first clinical data 
(safety and PK profile) from the administration schedule assessing weekly S64315 as a 
single agent, taking into account the anticipated activity, the limited DDI risk between 
S64315 and azacitidine and the potential risk of overlapping toxicity regarding the 
haematotoxicity and GI toxicity. Thus, following a conservative approach, the started 
dose of S64315 proposed to assess the combination of S64315 and azacitidine will be 
50 mg once a week as full tested dose. The dose escalation will be preceded by a 2-week 
lead-in dose (LID) period of weekly S64315 at a fixed dose of 25 mg for LID1 and 50 mg 
for LID2. 
The introduction of the LID period with fixed low doses of S64315 aims: 
 to allow an early detection of patients with cardiac sensitivity to S64315 and to prevent 
subsequent administrations with higher doses to these patients 
 to improve the overall tolerance to S64315 
 to reduce the risk of tumour lysis syndrome (TLS) 
 Azacitidine will be administered via subcutaneous injection at the dose of 75 mg/m², 
daily from day 1 to day 7, followed by a rest period of 21 days (28-day cycles), 
according to the current E.U SmPC. 
With regards to the administration schedule of the combination, there is an interest to 
administer azacitidine before the targeted dose of S64315 in order to sensitize the tumour 
cells to S64315 (Caenepell, 2018). For this reason, the administration schedule starting 
from cycle 1 onwards, over 28-day cycles is, as follows: 
 Azacitidine daily administered via a subcutaneous injection, from day 1 to day 7 (D1 to 
D7), followed by a rest period of 21 days 
 S64315 administered intravenously weekly, on day 2, day 9, day 16 and day 23 (D2, 
D9, D16, D23) 
 Expansion phase II part 
The dose of S64315 tested during the expansion phase II part will be the MTD/RP2D identified 
during the dose escalation phase I part, whichever the sub-arm (A1 or A2). 




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2.4.2. 
Rationale for the combination of a Mcl-1 inhibitor and a Bcl-2 inhibitor 
Given its selectivity for BCL-2, an intrinsic mechanism of venetoclax resistance is due to 
increased AML blast dependency on the anti-apoptotic proteins, BCL-xL and MCL-1. In the 
phase II trial of venetoclax monotherapy in relapsed/refractory AML patients, both BCL-xL 
and MCL-1 expression levels were negatively correlated with response to venetoclax 
(Konopleva, 2016). A numbers of novel therapies tested in pre-clinical models in combination 
with venetoclax have demonstrated synergistic eﬀects by downregulating MCL-1 expression 
(Sillar, 2019). 
Indeed, azacitidine has also been shown to reduce MCL-1 expression (Tsao, 2012). Hence, 
directly targeting MCL-1 makes logical sense in combination with a Bcl-2 inhibitor in AML. 
As proof of concept, a recent study investigated the role of BCL-2 and MCL-1 in AML survival 
by combining inducible lentiviral vectors expressing BH3-only proteins and venetoclax to 
differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as 
critical and complementary proteins regulating cell survival in acute myeloid leukaemia. Dual 
targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukaemia-bearing 
mice. Targeting BCL-2 and MCL-1 improved survival in a mouse xenograft model, whereas 
other combinations including BCL-2/BCL-XL/BCL-W or MCL-1 alone, did not. Hence, 
combining venetoclax with an MCL-1 inhibitor is an exciting prospect for the treatment of 
patients with AML (Teh, 2018). 
In pre-clinical studies, we have demonstrated the anti-leukemic efﬁcacy of a novel BCL-2 
inhibitor S55746 which demonstrates synergistic pro-apoptotic activity in combination with the 
MCL1 inhibitor S63845 (related analogue of S64315). Activity of the combination was caspase 
and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and 
active against a broad spectrum of poor risk genotypes, including primary samples from patients 
with chemoresistant AML. Co-targeting BCL-2 and MCL-1 was more effective against 
leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of 
activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of 
AML Figure (2.4.2) 1. Combined S55746 and S63845 suppresses leukaemia in vivo in NRG-
SG3 patient-derived xenograft models of AML but not normal hematopoietic cells in bone 
marrow of engrafted mice. 
Figure (2.4.2) 1 - Combined targeting of BCL-2 and MCL-1 improves the survival of mice  
xenografted with human AML 
 
These results suggest that targeting both BCL2 and MCL1 using small molecule inhibitors to 
suppress human AML in vivo may have less severe adverse effects on normal bone marrow 
hematopoietic function than standard cytotoxic drugs (Moujalled, 2019). 




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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. Primary objective 
Refer to Table (3.4) 1, Table (3.4) 2 and Table (3.4) 3. 
3.2. Secondary objectives 
Refer to Table (3.4) 1, Table (3.4) 2 and Table (3.4) 3. 
3.3. Exploratory objectives 
Refer to Table (3.4) 1, Table (3.4) 2 and Table (3.4) 3. 
3.4. Endpoints 
Table (3.4) 1 - Endpoints for dose escalation phase I part – Arm A 
 
Objectives 
Endpoints 
Primary 
To determine the safety profile and 
tolerability of S64315 in combination with 
azacitidine in patients with AML  
­ Incidence of DLTs starting from the LID 
period to the end of the first cycle of treatment 
of S64315 in combination with azacitidine 
­ Incidence and severity of AEs and SAEs 
according to NCI CTCAE v5.0 
­ Recording of any change or addition of a 
new concomitant treatment 
­ Laboratory tests: haematology with 
differential, blood biochemistry, thyroid 
function, blood coagulation, urinary analysis, 
hepatitis markers, TLS monitoring, cardiac 
markers follow up 
­ Complete physical examination, ECOG 
performance status, vital signs measurements 
­ ECG parameters, cardiac function 
assessment 
­ Left ventricular ejection fraction (LVEF) 
­ Dose interruptions, reductions and dose 
intensity 
Secondary 
To determine the PK profile of S64315 and 
azacitidine administered in combination, 
and potential metabolites 
PK parameters of S64315 and azacitidine 
administered in combination, and potential 
metabolites if applicable, in plasma (e.g. Cinf, tinf, 
AUClast, tlast, Clast, AUC, t1/2,z, CL and Vd) 
To evaluate the anti-leukemic activity of 
S64315 in combination with azacitidine 
­ CR rate, ORR (including CR/CRi/MLFS), 
Best Overall Response (BOR), Duration of 
Response (DOR), Progression Free Survival 
(PFS), Overall survival (OS) 
­ Anti-leukemic activity assessment using 
blood, BMA and BMB if available according to 
ELN 2017 response criteria (Döhner, 2017) 


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Objectives 
Endpoints 
Exploratory 
To assess MRD and clonal evolution after 
treatment with the combination of S64315 
with azacitidine 
Detection 
and 
quantification 
of 
residual 
leukemic cells by gene expression and genomic 
alterations analysis 
To evaluate the PD profile of S64315 in 
combination with azacitidine in relation to: 
 
­ the 
biological 
activity 
(target 
engagement) 
­ Leukemic blast reduction kinetic assessment 
 Absolute total and B lymphocyte count 
­ the relationship between the expression 
level of Bcl-2 family members (in blood, 
and bone marrow samples) and the anti-
leukemic activity 
­ Bcl-2 family member protein expression 
­ the relationship between the anti-
leukemic activity, karyotypes and AML 
associated 
genes 
mutations 
or 
dysregulations 
­ Somatic mutations, indels, rearrangements 
and amplifications and expression of BCL-2 
family member genes and in a panel of cancer-
related genes and karyotype analysis 
To explore PK/PD relationships for safety 
and efficacy 
PK/PD relationship related to haematological/ 
AE findings and to activity 
To explore relationships between DNA 
polymorphism for proteins involved in 
ADME and variability of PK parameters 
Pharmacogenomics on blood sample (optional 
part) 
Table (3.4) 2 - Endpoints for expansion phase II part – sub-arms A1 and A2 
 
Objectives 
Endpoints 
Primary 
To evaluate the CR rate of the combination 
of S64315 with azacitidine 
CR rate (proportion of patients who achieve 
CR) 
Secondary 
To assess anti-leukemic activity of the 
combination of S64315 with azacitidine 
­ ORR (including CR/ CRi and MLFS), BOR, 
DOR, PFS, OS 
­ Anti-leukemic activity assessment using 
blood/BMA and BMB if available according to 
ELN 2017 response criteria (Döhner, 2017) 
To determine the safety and tolerability of 
the combination of S64315 with azacitidine 
in patients with AML 
­ Incidence of DLTs  
­ Incidence and severity of AEs and SAEs 
according to NCI CTCAE v5.0 
­ Laboratory tests: haematology with 
differential, blood biochemistry, thyroid 
function, blood coagulation and urinary 
analysis, hepatitis markers, TLS monitoring, 
cardiac markers follow up 
­ Complete physical examination, ECOG 
performance status, vital signs measurements 
­ ECG parameters, cardiac function 
assessment 
­ LVEF 








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Figure (4.1.1) 1 - Study plan for S64315 administration schedule in combination with azacitidine (dose escalation phase I part – Arm A) 
 
 
 
 
 
S64315 infusion on D-13, D-6, CxD2, CxD9, CxD16, CxD23 
 
 
AZA: Azacitidine 
Azacitidine administration from CxD1 to CxD7 
 
 
 
D: day  
PK: pharmacokinetic measurements (see section 9.2) 
 
 
 
FU: post-withdrawal follow-up 
PD: pharmacodynamics measurements (see section 9.3) 
  
 
 
LID: Lead-in dose (see section 4.1.3.2)  
PG: optional pharmacogenomics measurements (see section 9.4) 
  
 
W: week 
 
 
 
 
 
 
 
 
 
WV: withdrawal visit 


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Figure (4.1.1) 2 - Overall study plan 
 
The study start is defined as the date of the first visit of the first patient, corresponding to ICF 
signature. It will be divided into the following periods for each patient of Arm A. 
Screening visit 
The screening eligibility criteria will be checked after the patient informed consent is obtained. 
Inclusion period 
The inclusion and exclusion criteria will be checked. The inclusion period can last up to 15 days 
before starting the LID period. The patient is included when he/she has met all the inclusion 
criteria. 
S64315 lead-in dose period 
The lead-in dose period will last 2 weeks. S64315 LID1 will be administered on D-13 at 25 mg 
and LID2 on D-6 at 50 mg. LID1 and LID2 doses will be fixed all along the study. 
Combination treatment period 
A treatment cycle will consist of 28 days for patients treated with S64315 in combination with 
azacitidine during the dose escalation phase I part: 
­ Weekly schedule for S64315 on CxD2, CxD9, CxD16 and CxD23 
­ Daily schedule for azacitidine from CxD1 to CxD7 followed by a 21-day rest period 
The administration schedule for the expansion phase II part will be defined according to what 
is observed during the dose escalation phase I part. 
The planned duration of combination treatment is until disease progression, unacceptable 
toxicity, treatment failure (defined as failure to achieve CR, CRi, PR, or MLFS after at least 
6 cycles of study treatment) or patient/physician decision. In case of myelosuppression within 
the context of non-active AML, a 4-week interruption of administration of one or both IMP(s) 
will be allowed for bone marrow recovery at the investigator’s discretion after discussion and 
approval from the Sponsor. 
If the patient is benefiting from the study treatment according to the investigator’s judgement 
and if it is in the patient’s best interest to continue the combination of S64315 with azacitidine, 
the patient may remain on study treatment. In case the patient becomes eligible for transplant, 
patient’s treatment discontinuation should be left at the investigator’s decision. 


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Withdrawal visit (WV): up to 28 days after the last dose of IMP 
Post-withdrawal follow-up 
After the withdrawal visit, a contact or telephone call will be done for the patients: 
­ every 3 months (±15 days) from the WV and up to 6 months, except in case of consent 
withdrawal for the dose escalation phase I part 
­ every 3 months (±15 days) from the WV and up to 12 months, except in case of consent 
withdrawal for the expansion phase II part 
End of Trial (EoT) 
The EoT is defined as the date of the last follow-up of the last patient (including a phone 
contact), or the date of the last contact attempt if the last patient is declared lost to follow-up. 
4.1.2. 
Investigation schedule 
Table (4.1.2) 1 describes the efficacy, safety and other assessments performed during the dose 
escalation phase I part of the study for Arm A. 
Investigation schedule for the expansion phase II part for sub-arms A1 and A2 will be further 
defined according to what is observed during the dose escalation phase I part. 
Investigation schedule for Arm B will further defined according to the results of Arm A. 










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E: (Safety measurements) In case of any troponin increase observed after any of the two first infusions of cycle 1, it will be recommended to assess cardiac markers at 48h and 
72h after S64315 EoI and after each subsequent infusion (before discharge and beyond, if needed), on a regular basis 
F: (Safety measurements) Applicable for all patients with a risk of developing TLS according to the investigator’s judgment: prior to each S64315 infusion (predose) and 2h, 
4h, 8h and 24h±2h after each S64315 EoI 
G: (Safety measurements) ECG predose could be performed within 24 hours before any S64315 infusion or after azacitidine before S64315 CXD2 infusion 
H: (Pharmacokinetic measurements) PK predose time points should be collected 5-30 minutes before infusion/injection; PK S64315 EoI time points should be collected within 
5 to 10 minutes before the end of infusion  
I: (IMP circuit) On days of concomitant administration of S64315 and azacitidine (CxD2), azacitidine should be administered 2 hours (±10 minutes) prior to S64315 
J: Except CPK-MB and BNP 
K: (Biochemistry) Assessments should be limited to AST, ALT and total bilirubin for 8h timepoints after LID1 and LID2 EoI, 8h, 24h and 72h timepoint after C1D2 EoI and 
24h timepoint after C1D9 EoI. Fasting conditions are not required for these timepoints. 
L: If Day 9 administration is not performed, all scheduled assessments should be performed at the next S64315 infusion (2nd S64315 infusion in cycle 1).  
*: Predose laboratory examinations to be performed within 3 days prior to LID1 or LID2, within 24h prior to S64315 C1D2 and within 3 days prior to any other IMP 
administration 
**: In case of an additional lead-in dose period (see section 6.1.2), all investigations must be performed except those for Pharmacokinetic and Pharmacodynamics measurements.  
 
 




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4.1.3. 
Dose escalation phase I part procedure for Arm A 
The following sections are applicable for the Arm A dose escalation phase I part. They will be 
updated for Arm B dose escalation phase I part, according to the results of Arm A. 
4.1.3.1. 
General points 
The sponsor will be responsible for the coordination of the clinical trial and will provide regular 
updates to the centres on the study progress. 
The dose escalation phase I part will be conducted in clinical centres which have a proven 
expertise in phase I studies in oncology. Multicentre study will allow improving patient’s 
recruitment. 
During the dose escalation phase I part, at each new dose level, the IMPs will be firstly 
administered to one patient. If no medically important or life-threatening toxicity occurs during 
a 1 week observation period, the subsequent patients will be allowed to start treatment without 
further delays between subsequent patients. The dose increase between two dose levels will be 
guided by the observed toxicities. 
A specific monitoring of potential cardiac, haematological, liver, etc. toxicities will be set up 
as described in section 8. 
4.1.3.2. 
Dose administration schedules 
The initial schedule will consist of a 2-week S64315 lead-in dose period followed by a 28-day 
cycle with the combination, i.e. a weekly regimen for S64315 and a daily regimen for 
azacitidine over 7 days. 
Alternative dosing schedules based on the observed clinical safety, PK/PD data and non-clinical 
data (in vitro, in vivo, PK/PD modelling data) may be further explored. They should be 
integrated in the protocol via an amendment. 
S64315 will be administered via intravenous (IV) infusion over at least 2h once every week, as 
follows: 
­ 2-week lead-in dose period i.e. fixed lead-in dose 1 (LID1) of 25 mg on D-13 and fixed 
lead-in dose 2 (LID2) of 50 mg on D-6 
­ followed by the combination treatment period over 28-day cycles, i.e. on CxD2, CxD9, 
CxD16 and CxD23 
The starting dose will be 50 mg. A panel of dose from 25 mg (-1) and up to 250 mg could be 
explored according to the dose escalation process of the BLRM. For more details, please refer 
to Table (4.1.3.3) 1. 
A minimum of 5 days between two infusions of S64315 is required. 
An infusion could be postponed in case of 1-day delay and should be discussed with the Sponsor 
in case of 2-day delay, for any reason other than medical / toxicity. 
Azacitidine will be administered during the combination treatment period at 75 mg/m² via 
subcutaneous (SC) injection, daily for 7 days, i.e. from CxD1 to CxD7, followed by a rest 
period of 21 days (28-day cycle). 
On days of concomitant administration of S64315 and azacitidine (CxD2), azacitidine should 
be administered 2h (±10 min) prior to S64315. 


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4.1.3.3. 
Dose escalation scheme 
An adaptive Bayesian Logistic Regression Model (BLRM) with overdose control (EWOC) will 
be used to guide the dose escalation of S64315 in combination with azacitidine. The dose 
escalation will only concern S64315. 
All available data on DLTs (assessed from the LID period and up to the end of cycle 1) will be 
used for updating the model. Before making a decision regarding dose escalation, the minimum 
number of patients required from a cohort must have been treated with one cycle of the 
combination and be fully evaluable for treatment-related toxicities according to the minimum 
requirements for inclusion in the Dose-Limiting Toxicity Evaluable Set (DLTES) (see 
section 4.1.3.5). If a patient is not eligible for inclusion in the DLTES, this patient must be 
replaced. 
The dose allocation methodology is detailed in section 10. 
A maximum of 6 DLT-evaluable patients may be initially enrolled at a new dose level, and a 
minimum of 3 DLT-evaluable patients must be treated at a given dose level in order to begin 
treatment of patients at a new, higher dose level. To better characterize the safety, tolerability, 
PK, PD, or preliminary clinical activity of S64315 in combination with azacitidine, more than 
6 DLT-evaluable patients may be treated in a cohort. If the starting dose of the combination is 
not well tolerated, a dose level-1 will be considered. Intermediate doses may be tested, if 
needed. For more details, please refer to Table (4.1.3.3) 1. A minimum of 6 DLT evaluable 
patients must have been evaluated at the dose considered to be the MTD, and before treating 
patients with this dose in the Phase II part of the study. 
Table (4.1.3.3) 1 - Provisional dose levels of S64315 
Dose level 
Proposed dose* 
Increment from previous dose 
-1** 
25 mg 
-50% 
1 
50 mg 
Starting dose 
2 
100 mg 
100% 
3 
200 mg 
100% 
4 
250 mg 
25% 
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts can be added 
at any dose level below or at the MTD in order to better understand safety, PK or PD 
**No dose reduction below dose level -1 is permitted for this study 
4.1.3.4. 
Intra-patient dose escalation 
Intra-patient dose escalation of S64315 is not permitted at any time within the first 4 cycles of 
treatment. After Cycle 4 is completed, individual patients may be considered for treatment at a 
dose of S64315 higher than the dose initially assigned. For a patient to be treated at a higher 
dose of S64315, he/she must have tolerated its originally assigned dose for at least the last 
4 cycles of therapy prior to the intra-patient dose escalation (i.e. he/she must not have 
experienced any S64315-related or S64315/azacitidine-related toxicity CTCAE Grade ≥ 2 at 
the originally assigned dose). Moreover, the newly assigned higher dose with which the patient 
is to be treated must have been validated, i.e. it should be a dose lower than the dose of the 
combination currently tested and considered safe according to the EWOC criterion at the time 
of the decision to escalate the dose of the patient. S64315 dose increase can occur as often as 
deemed necessary. For any further increase after the initial intra-patient dose escalation, the 
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Consultation and agreement with the Sponsor must occur prior to any intra-patient dose 
escalation. Data from the first cycle of treatment at the new dose levels will not be formally 
included into the statistical model describing the relationship between doses combined and 
occurrence of DLT. However, this data will be incorporated into the clinical assessment of 
safety within a dose escalation EoC meeting. 
4.1.3.5. 
DLT definition 
A dose-limiting toxicity (DLT) is defined as a clinically significant adverse event graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5.0, observed following the administration of the test drug, assessed as 
unrelated to disease progression, intercurrent illness, or concomitant medications, considered 
at least possibly related to the test drug by the investigator and that meets any of the criteria 
included in Table (4.1.3.5) 1. 
For each patient, an assessment of DLT will be performed at the end of the first cycle of 
treatment, through C1D28. This assessment will include all toxicities observed starting from 
the LID period through C1D28. Only DLTs occurring during the LID period + Cycle 1 will be 
included in the Bayesian logistic regression model (BLRM) that estimates the relationship 
between dose and DLTs. However, monitoring for DLTs that occur after Cycle 1 will continue, 
in case there is evidence for delayed or cumulative toxicity.  
Table (4.1.3.5) 1 - Toxicity criteria according to NCI CTCAE grading 
TOXICITY 
DLT CRITERIA 
Eye disorders: blurred 
vision; cataract; corneal 
ulcer; dry eye; eye pain 
Grade ≥ 3 confirmed by an ophthalmologic examination 
GI disorders 
Grade ≥ 3 nausea, vomiting or diarrhoea resulting in hospitalization, tube-feeding 
or use of total parenteral nutrition (TPN) 
Grade 4 diarrhoea  
Renal abnormalities 
Grade ≥ 3 serum creatinine  
Hepatic abnormalities 
AST or ALT ≥ 3xULN along with a total bilirubin > 2.0xULN and confirmed 
Hy’s law cases according to FDA guidance; 
For patients with elevated baseline AST or ALT or total bilirubin:  
[AST or ALT > 2.0xbaseline AND > 3.0xULN] OR [AST or ALT > 8.0xULN], 
whichever is lower, combined with [total bilirubin > 2.0 x baseline AND > 
2.0xULN] 
Isolated Grade 3 AST or ALT which does not resolve within 7 days to Grade ≤1  
 
Isolated Grade 4 AST or ALT 
For any Grade ≥3 hepatic toxicity which does not resolve within 7 days to Grade ≤ 1 level or baseline, an 
abdominal CT scan or hepatic echography must be performed.  
Pancreatic abnormalities 
Grade ≥ 3 serum lipase and/or serum amylase 
Grade ≥ 3 pancreatitis 
For any Grade 3 or Grade 4 pancreatic toxicity, which does not resolve within 7 days to Grade ≤1 level or 
baseline, an abdominal CT scan must be performed 
Creatine kinase (CK) / 
Creatine phosphokinase 
(CPK) 
Grade ≥ 3 serum CK/CPK  
Grade 3 isolated electrolyte abnormalities (i.e. those occurring without clinical 
consequence) not recovered with or without intervention, to Grade < 2 level 
within 72 hours 


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TOXICITY 
DLT CRITERIA 
Electrolyte 
abnormalities (including 
magnesium, calcium, 
phosphorus, etc.) 
clinically significant 
Any Grade 4 electrolyte abnormality 
Cardiac disorders 
QTcF interval ≥ 501 ms or increase of > 60 ms from baseline on at least two 
separate ECG assessments (1 assessment = triplicate ECG) 
Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline AND 
LVEF < 50% 
Asymptomatic, absolute decrease in LVEF of 20% or greater from baseline 
Troponin increase > 10xULN or a troponin increase consistent with the diagnosis 
of a myocardial infarction (Grade 3)  
Symptomatic congestive heart failure 
Skin and subcutaneous 
tissue disorders 
Grade ≥ 3 rash 
Haematological 
abnormalities 
Grade 4 neutropenia and/or thrombocytopenia persisting for 28 days after the start 
of azacitidine dosing in a cycle of therapy in the absence of active AML (< 5% 
blasts) or active MDS or myelofibrosis 
Other AEs 
Any Grade ≥ 3 AE 
Single event or multiple occurrences of the same event that lead to a dosing delay 
of > 7 days in a cycle may be considered to be DLT by the Investigators and the 
Sponsor, even if not Grade ≥ 3 
Failure to restart test drug administration at the same dose due to drug-related 
toxicity 
Failure to restart test drug administration at the same dose within one cycle (i.e. 
28 days) of the first missed dose due to delayed recovery from drug-related 
toxicity 
Failure to initiate cycle 1 after completing the LID period or failure to receive 
LID2 after receiving the LID1, due to drug-related toxicity  
NCI CTCAE v5.0 will be used for grading 
 
The following criteria will not be considered as DLT: 
­ Grade 3 nausea, vomiting, diarrhoea, anorexia or constipation that do not result in hospitalization, tube-feeding 
or use of TPN 
­ Grade 3 fatigue, asthenia, fever 
­ Grade 3 isolated electrolyte abnormalities (i.e. those occurring without clinical consequence) that resolve, with 
or without intervention, to Grade < 2 level in 72 hours 
Patients who meet any of the criteria included in Table (4.1.3.5) 2 at the end of Cycle 1 will not 
be evaluable for DLT and therefore will be replaced during the dose escalation phase I part of 
the study, but not in the expansion parts of the study. 
Table (4.1.3.5) 2 - Non evaluability criteria 
Permanently discontinued treatment before C1D28 for reasons other than DLT 
Did not undergo a DLT assessment at the end of Cycle 1 
Did not receive the minimum exposure criteria i.e. minimum number of doses according to the dose 
administration schedule of both IMPs prescribed from study entry to DLTs assessment visit (end of Cycle 1 D28), 
unless treatment was stopped for a DLT - see Table (4.1.3.5) 3 
If a patient received more than the assigned IMP doses from study entry to DLT occurrence during the DLT 
assessment period, non-evaluability criteria will be reassessed by Sponsor and investigator - see Table (4.1.3.5) 3 
 


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Table (4.1.3.5) 3 - Minimum number of S64315 and azacitidine doses to meet minimum exposure 
until the end of cycle 1 
Schedule description 
Minimum number of doses  
S64315 during the 2-week LID period (LID1 on D-13 
and LID2 on D-6) 
2 out of 2 
S64315 (D2, D9, D16 and D23 in 28-day cycle) 
3 out of 4 
Azacitidine (D1 to D7 in 28-day cycle) 
5 out of 7 
4.1.3.6. 
DLT management 
Study treatments must be delayed for any patient who experienced a DLT. Conditions to resume 
treatment are described in section 8.12. 
All DLT will be reported to I.R.I.S. within 24h via the DLT form in the electronic Case Report 
Form (eCRF). The eCRF ‘Adverse Event’ page should then be filled in, without waiting for the 
results of the clinical outcome or of additional investigations. When data of the DLT form are 
submitted, an e-mail will be immediately and automatically sent to the sponsor. 
If the eCRF is unavailable when the investigator is informed of the DLT, he/she should: 
­ report the DLT on a paper ‘DLT form’ 
­ send the form by fax immediately to I.R.I.S. at the following number: +33.1.55.72.50.04 
As soon as the eCRF becomes available again, the investigator must enter the data in the eCRF. 
4.1.3.7. 
Decision process and decision rules 
Before testing a new dose level during the dose escalation phase, an EoC meeting between the 
Sponsor (Therapeutic Area Oncology and Immuno Oncology, Medical Safety Leader, 
Methodology Department and Clinical Pharmacokinetics department), the coordinator and the 
investigators will take place to discuss the toxicities in terms of DLTs, safety data, the PK and 
available PD and the preliminary efficacy data observed in all patients. This meeting will 
support the decision to escalate to the next dose level of the treatment, to decide jointly of the 
next dose level to be tested, the go/no go for the expansion phase II part. 
If a dose/treatment schedule has not yet been tested, a one-week period should be respected 
between the C1D2 of the first patient and the C1D2 of subsequent patients of the cohort 
(between the first and the second infusion in patient of S64315 at the full tested dose). If no 
medically important or life-threatening toxicity occurs during the one-week observation period, 
the subsequent patients will be allowed to start treatment without further delays between 
subsequent patients. 
A template of ‘Dose allocation meeting minutes’ is available in Appendix 6. 
A Data Safety and Monitoring Board (DSMB) will be set up and will review the safety data 
before each EoC meeting and provide recommendations to the Sponsor. 
4.1.4. 
Expansion phase II part for sub-arms A1 and A2  
The RP2D of S64315 in combination with azacitidine and its administration schedule will be 
defined according to results observed in the dose escalation phase I part in terms of safety, 
activity and, if appropriate, PK data. 
 
The expansion phase II part will be divided in two distinct parts according to a Bayesian two-
stage design: stage 1 and stage 2. 


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A futility analysis will be performed at the end of stage 1 for sub-arms A1 and A2 based on the 
rate of CR observed after 4 cycles of combination treatment. This analysis will support the 
decision to stop the evaluation of the combination or to continue the evaluation during the stage 
2. The rationale for the expansion phase II part design is described in section 2.3.7. 
Up to 50 patients will be treated in each sub-arm (A1 and A2) at the RP2D as follows (more 
detail on this topic is provided in section 10.5.2 and Appendix 8): 
­ Twenty-three patients will be treated in the first stage of analysis; if there is evidence that 
the CR rate is < 20% (if there are fewer than 5/23 patients who achieve a CR), treatment will 
be stopped in the relevant arm 
­ If there is evidence that the CR rate >= 20%, 27 additional patients will be treated to better 
estimate the rate of CR.  
After at least 4 patients have been treated during dose expansion at the RP2D, if the observed 
rate of DLT through the end of Cycle 1 exceeds 33% (including the patients treated at this dose 
during dose escalation), the BLRM will be updated to determine whether the RP2D still satisfies 
the EWOC principle. If the RP2D is estimated to have a ≥25% posterior probability of 
generating excessive toxicity (DLT rate between 33% and 100%) during the first cycle of 
treatment, then enrollment to the study will be paused. A risk assessment will be conducted by 
the DSMB, the investigators and sponsor, and consideration will be given to reducing the 
RP2D.  
In addition, monitoring will continue for DLTs that may occur after the first cycle of treatment. 
After at least 4 patients have had the opportunity to receive a second cycle of treatment, if the 
posterior probability is greater than 25% that the true rate of DLT occurring after Cycle 1 
is >33%, enrollment to the study will be paused. Patients should have received at least three 
doses of S64315 from Cycle 2 to be evaluable, unless dosing was limited by the occurrence of 
a DLT. Evaluable patients treated at this dose during escalation will also be included in this 
assessment. The study will also be paused if the cumulative rate of Grade ≥3 treatment-related 
cardiac adverse events at the RP2D exceeds 20%. In either case, the safety of the RP2D will be 
re-evaluated by the DSMB, the investigators and sponsor, and consideration will be given to 
reducing the RP2D.   
More detail on this topic is provided in section 10.3.2. 
4.2. Measures to minimise bias 
During the study: 
­ International multicentre study 
­ Triplicate 12-lead ECGs will be recorded on site and analysed by a central reading CRO for 
ECGs tracings 
­ PK sample analyses will be performed in a specific central laboratory, which will minimise 
the variability of measurements 
­ PD sample analyses (protein and gene expression, gene alteration and determination of 
complex dissociation analysis) will be centrally stored and sent to a specific analytical centre 
for analyses, to minimise the variability of measurements 
­ Genes implicated in ADME analyses (optional) will be performed in a specific central 
laboratory 


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4.3. Study products and blinding systems 
4.3.1. 
Products administered 
Arm A 
S64315 (test drug) and azacitidine administered in combination are both IMPs in Arm A. 
Azacitidine will be provided as marketed boxes. 
Les Laboratoires Servier Industrie (Gidy, France) will: 
­ pack, release and supply S64315 Therapeutic Units (TUs); 
­ relabel, release and supply azacitidine marketed boxes. 
Table (4.3.1) 1 provides a description of the IMPs. 
Table (4.3.1) 1 - Description of the IMPs (S64315 and azacitidine) 
 
S64315 
Organic concentrate 
S64315 
Liposomal vehicle 
Azacitidine 
Pharmaceutical form 
Concentrate of solution for 
infusion 
Intravenous infusion 
Powder for suspension 
for injection 
Unit dosage 
209.95 mg/3.4mL 
2.39 gram of egg 
phospholipids in 
23.9 mL 
100 mg 
Appearance, colour 
Colourless to greenish, 
yellowish or slightly 
brownish, clear solution 
A yellow to brown turbid 
solution 
White lyophilized 
powder 
Composition 
Each vial contains an overfill 
volume of 0.4 mL, so it 
actually contains 234.65 mg 
of S64315. The vials contain 
a clear, colourless to greenish, 
yellowish or slightly 
brownish solution comprising 
of the active ingredient 
S64315, propylene glycol, 
anhydrous ethanol, DMPG 
(1,2-Dimyristoyl-sn-1-
glycero)-3-phospho-rac-
glycerol sodium salt), PEG 
300 (Polyethylene glycol 300) 
Each vial contains 
2.39 gram of egg 
phospholipids. The 
liposomal vehicle 
comprises egg 
phospholipids, sucrose, 
L-histidine and water for 
injections. Sodium 
hydroxide for injections 
and hydrochloric acid are 
also used for pH 
adjustment. 
The egg phospholipids 
comprising liposomal 
vehicle form small 
liposomes in aqueous 
environment and are 
used as a solubilizing 
vehicle, able to dissolve 
S64315 in an aqueous 
environment after 
mixing with S64315 
liquid in the vial 
Each vial contains 
100 mg azacitidine. 
After reconstitution, 
each mL of suspension 
contains 25 mg 
azacitidine. 
 
Excipient: < 
 
Table (4.3.1) 2 provides a description of the packaging of the IMPs. 






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4.4. Discontinuation of the study 
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. Stopping rules during the study are described in section 8.12 for any patient 
throughout the study, in section 10.2.7 for the dose escalation phase I part, in section 10.3 for 
the expansion phase II part and in section 4.4.2. Moreover, the DSMB could also give 
recommendations, based on the review of the safety data, to suspend or to prematurely terminate 
the study/treatment arms in case of serious concerns about patient safety. 
After having informed the coordinator, the sponsor or the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) or the Competent Authorities may terminate the 
study before its scheduled term. Two copies of the written confirmation will be dated and signed 
by the coordinator. The IRB/IECs and Competent Authorities will be informed according to 
local regulations. 
If the study is prematurely discontinued, the ongoing patients should be seen as soon as 
possible, and the same assessments as described in section 5.8 should be performed. 
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 patient’s 
interests. 
In case of study suspension (temporary halt), the study may resume once concerns about safety, 
protocol compliance and data quality are addressed and satisfy the Sponsor, the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and Competent Authorities. 
4.4.2. 
Criteria for stopping or pausing the study 
The study will be paused and the health authorities will be notified if: 
­ Any death suspected to be related to S64315 occurs within 30 days of study treatment 
administration  
­ The observed cumulative rate of Grade ≥3 treatment-related cardiac adverse events at the 
RP2D (including patients treated in both dose escalation and dose expansion) exceeds 20%, 
after at least 4 patients have been treated with S64315 in dose expansion 
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 reports, clinical laboratory examination reports and all other 
patients’ examination results, copies of karyotype reports, requisition forms, registration forms, 
exam recording (and the result report when applicable) provided by the CRO to the centre, and 
the result report when applicable, 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. 


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5. SELECTION AND WITHDRAWAL OF PATIENTS 
The criteria for dose escalation phase I part of Arm A are defined hereafter and should be 
adapted for expansion phase II part (sub-arms A1 and A2) according to results observed in the 
dose escalation phase I part. The criteria will be defined later for Arm B according to the results 
of Arm A. 
5.1. Screening criteria 
5.1.1. 
Demographic characteristics 
1. Patients aged ≥ 18 years 
5.1.2. 
Medical and therapeutic criteria 
2. a. Patients with cytologically confirmed and documented de novo, secondary or therapy-
related AML as defined by WHO 2016 classification (Arber, 2016) excluding acute 
promyelocytic leukaemia (APL, French-American-British M3 classification) with: 
­ relapsed or refractory disease and without established alternative therapy or 
­ secondary to MDS without established alternative therapy  
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Appendix 3) 
5.1.3. 
Informed consent 
4. Written informed consent obtained prior any study-specific procedure as described in 
section 13.3 
5.2. Non-screening criteria 
5.2.1. 
Medical and therapeutic criteria 
5. Previous myeloproliferative syndrome (MPS) 
6. Criterion deleted in Substantial Amendment #1 (Amended Protocol V. 2.0) 
7. Patients previously treated with any Mcl-1 inhibitor 
5.2.2. 
General criteria 
8. Pregnant and lactating women 
9. Unlikely to cooperate in the study  
10. Participation in another interventional study requiring investigational treatment 
administration at the same time or within 2 weeks or at least 5 half-lives (whichever is 
longer) prior to the first IMP administration; participation in non-interventional registries 
or epidemiological studies is allowed. In case of biologic agents with a long half-life such 
as CART cells, immune checkpoint inhibitors, bispecific antibodies, a washout of 28 days 
is allowed 
11. Patients already enrolled in the study (informed consent signed) and treated in the study 


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5.3. Inclusion criteria 
5.3.1. 
General criteria 
12. ECOG performance status ≤ 2 (Appendix 3) 
13. Women of childbearing potential (WOCBP) must use a highly effective method of birth 
control (described in section 5.5), during study and up to 6 months after the last IMP 
administration. In case of use of oral contraception, women should have been stable on the 
same contraceptive drug (i.e. same active principle) for at least one month prior to the first 
IMP administration 
14. Men with WOCBP partners must use a condom during the study and up to 3 months after 
the last IMP administration. In addition, contraception should be considered for their female 
partners. Contraceptive measures do not apply if the patient is sterile, vasectomized or 
sexually abstinent. Sperm donation will not be allowed during the study and up to 3 months 
after the last IMP administration 
5.3.2. 
Medical and therapeutic criteria 
15. Adequate haematological function based on the last assessment performed within 7 days 
prior to the first IMP administration, defined as: 
- Circulating white blood cell count < 10 G/L (only use of hydroxycarbamide or 
leukapheresis before study drug initiation is allowed to achieve this inclusion criterion) 
16. a. Adequate renal function based on the last assessment performed within 7 days prior to 
the first IMP administration defined as calculated creatinine clearance > 60 mL/min/1.73m², 
determined by MDRD (Appendix 4) 
17. Adequate hepatic function based on the last assessment performed within 7 days prior to 
the first IMP administration defined as: 
- AST and ALT < 1.5 x ULN and 
- Total serum bilirubin level < 1.5 x ULN, except for patients with known Gilbert’s 
syndrome (confirmed by the UGT1A1 polymorphism analysis) who are excluded if total 
bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
5.4. Exclusion criteria 
5.4.1. 
General criteria 
18. Women of childbearing potential (WOCBP) tested positive in a serum pregnancy test within 
7 days prior to the first day of IMP administration 
19. Patients who have not recovered from toxicity of previous anticancer therapy, including 
Grade ≥ 2 toxicity (except alopecia of any grade) according to the National Cancer Institute 
Common Terminology Criteria for Adverse Event (NCI CTCAE) v5.0, prior to the first 
IMP administration 
5.4.2. 
Medical and therapeutic criteria 
20. Severe or uncontrolled active acute or chronic infection 
21. Uncontrolled hepatitis B or C infection 
22. Known carriers of HIV antibodies 
23. Known history of significant liver disease 
24. Known active acute or chronic pancreatitis 
25. Known active central nervous system disease 
26. Clinically active severe skin diseases 


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27. Major surgery within 4 weeks prior to the first IMP administration or patients who have not 
recovered from side effects of the surgery 
28. History of myocardial infarction (MI), unstable angina pectoris or coronary artery bypass 
graft (CABG) within 6 months prior to first IMP administration 
29. a. Troponin I > ULN or Troponin T > ULN if Troponin I cannot be assessed 
30. Clinically significant cardiac dysfunction (including NYHA class ≥II heart failure, Left 
Ventricular Ejection Fraction (LVEF) < 50% as assessed by echocardiography (ECHO) or 
Multi-Gated Acquisition (MUGA) scan) 
31. QT prolongation defined as QTc interval (corrected with Fridericia’s formula) > 450 ms for 
males and > 470 ms for females, obtained from triplicate 12-lead ECG 
32. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as 
heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT 
syndrome or unexplained sudden death under 40 years of age 
33. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia, atrial fibrillation), 
complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz 
type II and third degree AV block) 
34. Uncontrolled arterial hypertension (SBP > 150 mmHg or DBP > 95 mmHg) 
35. Unresolved CTCAE Grade ≥ 2 diarrhoea or presence of medical condition associated with 
chronic diarrhoea (such as irritable bowel syndrome or inflammatory bowel disease) 
36. Coagulopathy that will increase the risk of bleeding complications according to 
investigator’s judgment (e.g. disseminated intravascular coagulation) 
37. Allogenic stem cell transplant within 3 months before the first IMP administration and/or 
patients who still receive immunosuppressive treatment and/or patients with active Graft-
versus-host disease 
38. Any previous anti-leukemic treatment for the studied disease within 2 weeks or at least 
5 half-lives (whichever is longer) of this treatment prior to the first IMP administration 
(except for hydroxycarbamide). In case of donor lymphocyte infusions following allogeneic 
haematopoietic stem or investigational biologic agent with a long half-live such as CART 
cells, immune checkpoint inhibitors or bispecific antibodies, a wash-out of 28 days will be 
acceptable 
39. Any radiotherapy within 2 weeks prior to the first IMP administration (except for palliative 
radiotherapy at localised lesions) 
40. Malignant disease other than that being treated in this study. Exceptions include 
malignancies that were treated curatively, have not recurred within 2 years prior to study 
entry and not requiring ongoing therapy, completely resectable basal cell and squamous cell 
skin cancers, any malignancy considered to be indolent and that has never required therapy 
and completely resected carcinoma in situ of any type 
41. Any clinically significant medical condition (e.g. organ dysfunction) or laboratory 
abnormality likely to jeopardize the patients’ safety or to interfere with the conduct of the 
study, in the investigator’s opinion 
42. History of severe allergic or anaphylactic reactions to azacitidine or history of 
hypersensibility to excipient of S64315 or azacitidine, including egg, soybean, liposomal 
vehicle excipients or mannitol (E421) 
43. b. Patients receiving treatment medications listed in section 6.3.1 and that cannot be 
discontinued at least 1 week prior to the first IMP administration (at least 2 weeks for 
CYP3A4 inducers, see section 6.3.1 for details) and during the study period. Patients having 
received calcineurin inhibitors within 4 weeks before the first IMP administration. 
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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 patient), bilateral tubal occlusion, male sterilization (vasectomy). 
­ Definition of acceptable contraception methods for the study: 
Acceptable contraception methods for the study are those considered as highly effective 
methods, male or female condom with or without spermicide, cap, diaphragm or sponge with 
spermicide. 
5.6. Retest management during screening period 
A patient who has a laboratory result that does not satisfy the entrance criteria may have the 
test repeated providing that the investigator judges it relevant according to the patient previous 
result 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 will not be required to sign another informed consent and the original patient 
identification number assigned by the investigator will be used. 
In any case, the last result available for each parameter must be considered for the patient 
inclusion. 
5.7. Additional information recorded at the inclusion visit 
Not applicable 
5.8. Patient withdrawal 
5.8.1. 
Withdrawal criteria 
Information to be collected during the last visit of these patients is given in section 5.8.2. These 
follow-up modalities are used to ensure the efficacy and safety evaluation of all patients who 
received the IMPs. 


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The reasons for premature discontinuation of IMPs are: 
­ Adverse events incompatible with continuation of one of the IMPs according to the 
judgment of the investigator, including no recovery in safety parameters. Criteria for 
treatment discontinuation are implemented during the LID period in order to avoid treating 
a patient in medical condition that could jeopardize his/her safety or interfere with the 
conduct of the study. If the patient cannot receive the LID2 or the first S64315 C1D2 dose 
due to an AE, the S64315 infusion (either LID2 or C1D2) may be postponed by 1 to 5 days. 
If the LID2 is postponed for more than 2 days (5 days maximum), the C1D2 dose may not 
be postponed for more than 2 days. If S64315 C1D2 is postponed, azacitidine C1D1 dose 
should be postponed as well, whenever possible. If the AE has not recovered within this time 
period, the patient must be withdrawn from the study. 
­ Pregnancy (for reporting, see section 8.9.2.3) 
­ Protocol deviation if it interferes with the study evaluations and/or if it jeopardises patient’s 
safety, e.g. any medical event requiring administration of an unauthorised concomitant 
treatment (see section 6.3) 
­ Disease progression at the discretion of the investigator 
­ Treatment failure, defined as failure to achieve CR, CRi, MLFS or PR after at least 6 cycles 
of study treatment 
­ Non-medical reason (to be thoroughly described) e.g. consent withdrawal, patient’s 
removal 
­ Other, physician decision (for reasons that cannot be included in any of the criteria listed 
above, for example: availability of a better therapeutic alternative for the patient) 
If the patient becomes eligible for transplant, patient treatment discontinuation should be left to 
the investigator’s decision. 
If the patient is benefiting from the study treatment according to the investigator’s judgement 
and if it is in the patient’s best interest to continue the combination of S64315 with azacitidine, 
the patient may remain on study treatment. A patient must discontinue the combination if the 
toxicity recurs with the same or worse severity after resumption of dosing, unless the 
investigator decides it is in the patient’s best interest to continue the combination of IMPs and 
upon documented agreement with the Sponsor. 
If one IMP is permanently discontinued, both drugs should be permanently discontinued. A 
patient must be withdrawn from the study if one the IMPs is interrupted for more than 
28 consecutive days from C1D2, for any reason. However, for patients with LVEF decline, IMP 
interruptions of up to 35 consecutive days are permitted. 
5.8.2. 
Procedure 
Upon discontinuation of the IMPs, the investigator must: 
­ notify the Sponsor immediately by recording this information in the eCRF 
­ indicate the main reason, if there are several reasons 
Patients should return for the Withdrawal visit (WV) as soon as possible and up to 28 days of 
the last dose of IMP. If the decision to discontinue occurs at a regular scheduled visit, that visit 
may become the WV rather than having the patient returns for an additional visit. 
After the withdrawal visit, patients will continue in the follow-up period; the date of death and 
the progression date will be recorded in the eCRF, if applicable. Study discontinuation for 
another reason than disease progression will be recorded in the eCRF. 


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In the case of premature withdrawal from the study due to an AE (event requiring immediate 
notification or not), the investigator must make every effort to collect the information relating 
to the outcome of the AE. If necessary, the information will be collected afterwards (see 
section 8.9). This information is recorded in the ‘AEs’ eCRF form. If the investigator cannot 
collect the information during a patient visit, he must collect it from the patient’s doctor in 
charge of his/her follow-up. 
If the study is stopped/one of the IMPs is discontinued as a result of an event requiring 
immediate notification, the procedure described in section 8.9.2.5 is to be implemented. 
The dispositions to be taken after the IMPs discontinuation are described in section 6.5. 
5.8.3. 
Lost to follow-up 
When the investigator has no news of the patient, he/she must make every effort to contact 
him/her or a person around him/her (phone calls, letters including registered ones, etc.), to 
establish the reason of the IMPs discontinuation and suggest to the patient to come to a 
withdrawal visit. If all these attempts to contact the patient fail, the investigator can then declare 
the patient ‘lost to follow-up’. The investigator should document all these attempts in the 
corresponding medical file. 
6. TREATMENT OF PATIENTS 
The following sections are applicable for dose escalation phase I part of Arm A and. They 
could be refined for expansion phase II part (sub-arms A1 and A2) according to results 
observed in the dose escalation phase I part, as well as for Arm B according to the results of 
Arm A. They will be described in an amendment to the protocol. 
6.1. IMPs administered 
6.1.1. 
IMP administration schedule 
S64315 and azacitidine will be administered in combination in patients with AML. The 
administration schedule of the combination is detailed in section 4.1.3.2. 
Azacitidine will be administered via SC injection, once a day over 7 days i.e. from CxD1 to 
CxD7, followed by a rest period of 21 days, over 28-day cycle during the combination treatment 
period, according to E.U. SmPC recommendations. 
S64315 will be administered via IV infusion over at least 2h, once a week, i.e. during the 2-
week lead-in dose period (on the days of LID1 and LID2) and then during the combination 
treatment period on CxD2, CxD9, CxD16, and CxD23 over 28-day cycle. 
As data will emerge during the study regarding clinical safety and PK data, the administration 
schedule and the infusion duration may be changed. Any change will be implemented through 
an amendment to the protocol. 
The assignment of a patient to a particular cohort will be coordinated by the Sponsor. No 
randomisation will be performed in this study. Information about infusion duration as well as 
treatment schedule will be reported in the Patient Registration Form (Appendix 2). 
For IMP dose adaptations due to toxicities, please refer to section 8.12. 


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6.1.2. 
Administration/re-administration criteria 
­ Criteria to fulfil before each S64315 infusion 
 Before each S64315 infusion, biological parameters should be checked in order to detect 
any toxicity (see Table (8.12) 1) 
 Patients with Grade ≥ 2 hypo/hypercalcemia and/or hypo/hypermagnesia and/or 
hypo/hyperkalaemia despite attempts at medical correction should not be treated with 
S64315 
 Patients with WBC ≥ 10 G/L despite attempts at medical correction should not be treated 
with S64315. Hydroxycarbamide can be used to reduce the circulating blast count before 
and throughout the treatment period 
 AST and ALT ≤ 3 x ULN (except for LID1: AST and ALT ≤ 1.5 x ULN) 
 Total bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert’s syndrome, 
who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
 In the case of an S64315 interruption ≥ 28 days, its readministration must be preceded by 
a lead-in dose period (except for patients in CR/CRi) which is called additional Lead-In 
dose period. See Table (4.1.2) 1 for more details on safety assessments required. 
­ Criteria to fulfil before each first azacitidine administration (i.e. CxD1) 
Patients should be monitored for haematological toxicity and renal toxicities. A delay in starting 
the next cycle or a dose adjustment due to haematological toxicity and/or renal toxicity may be 
necessary according to E.U. SmPC (see Table (8.12) 2). WBC, absolute neutrophil count 
(ANC), platelets, serum creatinine, BUN and serum bicarbonate will be assessed before starting 
the next treatment cycle. 
6.2. IMP dispensing 
S64315 and azacitidine 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 S64315, as well as the description 
of the tubing and infusion sets compatible with S64315, are described in the Pharmacy Manual. 
All dosages of S64315 and azacitidine prescribed to the patient and all dose changes during the 
study must be recorded in the eCRF. 
The detachable portion of the label on the IMPs box must be stuck by the 
investigator/responsible person 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 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited. Concomitant medication 
administration could result in DDI that could potentially lead to reduced activity or enhanced 
toxicity of the concomitant medication, as of S64315 and/or azacitidine. 


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A list of prohibited and unauthorized treatment by drug class can be consulted in the eCRF, it 
includes the ‘guidance on use of co-medications for clinical study CL1-64315-004’ to be used 
as reference before prescribing any concomitant treatment to a patient. Patients must not have 
taken calcineurin inhibitors for at least 4 weeks before the first dose of S64315 in order to be 
eligible. 
Before any new concomitant medication administration, the investigator should assess any 
potential DDI with S64315 and azacitidine (if applicable) using this concerned medication 
SmPC, from 7 days before the first IMP intake to 7 days following last IMP intake. For CYP3A4 
inducers comedications, the wash out period is defined as at least 2 weeks. For concomitant 
CYP3A4 inducer drugs with a long elimination half-life (> 40 h), a wash out period of 1 week 
and additional 5 half-lives must be applied before initiation of S64315 therapy.  Contraindicated 
comedication drugs with a long elimination half-life are flagged in the “Guidance on use of 
comedication for clinical study CL1-64315-004” that can be consulted in the eCRF. 
Regularly updated lists of the co-administered medications that should be contraindicated or 
used with caution will be shared through the eCRF during the clinical study. These lists are not 
exhaustive and only meant to be used as a guide (for example, pro-drugs of the listed drugs 
should be considered as their active substance). The Sponsor should be contacted in case of any 
doubt. If a medication appears on both ‘prohibited’ and ‘to be used with caution’ lists, the 
medication is prohibited. 
6.3.1. 
List of prohibited medications during the IMP treatment period 
Medications prohibited from at least 7 days before the first IMP administration and up to 7 days 
following the last IMP administration: 
­ Strong CYP3A4 inducers 
­ Dual strong CYP3A4 and CYP2C8 inhibitors and inducers 
­ Listed dual ‘strong CYP3A4 inhibitors’ and ‘CYP2C8 and/or P-GP inhibitors’ 
­ Listed herbal preparations/medications 
­ OATP substrates 
­ QT prolonging drugs with a known risk to induce Torsades de Pointes (TdP) 
­ Other investigational and anti-leukemic therapies 
Medications prohibited from 7 days before the first IMP administration and up to the end of 
cycle 1: 
­ Haematopoietic growth factors 
6.3.2. 
List of medications to be used with caution during the IMP treatment period 
Medications to be used with caution from at least 7 days before the first IMP administration 
and up to 7 days following the last IMP administration: 
­ Strong CYP3A4 inhibitors 
­ Moderate CYP3A4 inducers 
­ Dual P-GP inhibitors and strong/selected moderate CYP3A4 inhibitors 
­ Drugs with possible and conditional risk for TdP 
Medications to be used with caution during the IMP treatment period: 
­ CYP2C8 sensitive and Narrow Therapeutic Index (NTI) substrates 
­ Multi-transporter substrates (including OATPs) with no reported in vivo DDI reported 
­ MATE1 sensitive and NTI substrates 


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­ BCRP substrates (IV administration) 
­ P-GP NTI substrates 
­ Warfarin (unknown risk for plasma proteins displacement due to co-administration of 
S64315, leading to higher free concentrations of warfarin (Prothrombin Time and 
International Normalized Ratio (PT/INR) monitoring is required) 
­ Listed herbal preparations/medications 
The information regarding the administration of such medications, the occurrence of therapeutic 
drug monitoring, the need of dose adaptation and the magnitude of the adaptation when 
applicable must be recorded in the eCRF. 
6.3.3. 
List of permitted concomitant medications 
­ Hydroxycarbamide used to control leucocytosis is allowed 
­ Haematopoietic growth factors used in the centre may be prescribed after Cycle 1 for the 
subsequent cycles 
­ Anti-emetics are strongly recommended for prophylaxis prior each S64315 administration 
and dexamethasone mandatory at least before S64315 LID1, LID2 and CID2 (see 
section 8.2.8.1) 
­ Anti-diarrhoeals should be prescribed if clinically indicated except for prophylaxis prior to 
first dose of S64315. If prophylaxis or treatment is required subsequently to the first S64315 
administration, it may be administered at the discretion of the investigator (see 
section 8.2.8.2) 
The patient must be informed to notify the investigational site about any new medications 
he/she takes after having signed the ICF of the study. All medications (other than IMPs) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed in the eCRF. 
Treatments received for the studied disease and after the last IMPs administration are to be 
recorded in ‘Post-withdrawal follow-up’ eCRF form. 
6.4. IMP compliance 
The number of vials and volume infused are to be counted by the investigator or a designated 
person from his/her team and recorded in the eCRF and on the therapeutic unit tracking form, 
or an equivalent document. 
The compliance will be assessed from the method described above. 
6.5. IMP discontinuation 
After the discontinuation of the IMPs, patient’s treatment is left to the physician’s discretion. 
S64315 is not licensed and not available on the market. Azacitidine is licensed and available on 
the market. 
Specific rules may be followed in some countries according to local regulation. 


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7. ASSESSMENT OF EFFICACY 
The efficacy assessments hereafter are applicable for dose escalation phase I part of Arm A 
They could be refined for expansion phase II part (sub-arms A1/ A2) according to results 
observed in the dose escalation phase I part, as well as for Arm B according to the results of 
Arm A. They will be described in an amendment to the protocol. 
7.1. Efficacy measurements 
Efficacy measurements performed during the study will use AML criteria: ‘Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert 
panel’ (Döhner, 2017) (Appendix 5). They are described in Table (4.1.2) 1. 
7.2. Methods and measurement times 
­ A full blood count and blood film examination will be assessed for treatment response at the 
following time points: 
 Baseline 
 C1D1 azacitidine predose (within 24h prior to C1D1) 
 C1D2 4h after S64315 EoI 
 C1D3 and C1D4 azacitidine predose (ideally in the morning) 
 From Cycle 2 onwards: D1 azacitidine predose of each cycle (within 3 days prior to 
CxD1) 
 WV 
­ A bone marrow aspirate (BMA) and/or a bone marrow biopsy (BMB) (according to local 
medical practice) will be assessed at the following time points: 
 Baseline 
 C2D1 azacitidine predose (within 2 days prior to C2D1) 
 C3D1 azacitidine predose if non-CR/CRi on C2D1 (within 7 days prior to C3D1) 
 C7D1 azacitidine predose if non-CR/CRi/MLFS or PR at any previous cycle (within 7 
days prior to C7D1) 
 Any time if clinically indicated or in case of suspected disease progression at the 
investigator’s discretion 
 WV 
8. ASSESSMENT OF SAFETY 
The safety assessments hereafter are applicable for dose escalation phase I part of Arm A They 
could be refined for expansion phase II part (sub-arms A1/ A2) according to results observed 
in the dose escalation phase I part, as well as for Arm B according to the results of Arm A. 
They will be described in an amendment to the protocol. 
All adverse events and other situations relevant to the safety of the patients must be followed 
up and fully and precisely documented, in order to ensure that the sponsor has the needed 
information to continuously assess the benefit-risk balance of the clinical trial. 


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Table (8) 1 - Mitigation strategies of the identified risks 
Risk 
Mitigation strategy 
Cardiac 
See section 8.2.5 
ECG recording 
Echocardiography and GLS / MUGA scan 
Cardiac markers 
MRI 
Holter 
Hepatic 
See section 8.2.6 
Gastrointestinal 
See section 8.2.8 
TLS 
See section 8.2.9 
IRR 
See section 8.2.10 
8.1. Specification of safety parameters 
Safety measurements of S64315 in combination with azacitidine performed are indicated in 
Table (4.1.2) 1. They include: 
­ DLTs assessment at the end of Cycle 1 (DLTs will be continued to be monitored at all 
cycles), which will drive the MTD/RP2D identification 
­ Record of AEs and toxicity according to NCI CTCAE. The severity of each AE will be 
graded according to version 5.0 on a five-point scale (Grade 1 to 5) 
­ Recording of any change or addition of a new concomitant medication 
­ Laboratory tests: haematology, blood biochemistry, blood coagulation parameters, 
urinalysis, hepatitis markers, TLS monitoring, cardiac marker follow up 
­ Local assessment of ECGs by the investigators and central ECG reading 
­ LVEF evaluation by echocardiography or MUGA scan; Global Longitudinal Strain (GLS) 
assessment will be assessed during the echocardiography, whenever possible (not 
mandatory), as a means to follow left ventricular systolic dysfunction at the time points 
already defined in the study protocol for echocardiography 
­ Physical examination, ECOG PS (Appendix 3), vital signs measurements 
­ Pregnancy test for women of childbearing potential 
Any significant abnormality detected during safety assessments from the patient ICF signature 
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 make 
an individual unsuitable for inclusion: 
­ Initial diagnosis, relevant medical history at screening (baseline) 
­ Previous chemotherapies, bone marrow transplants, surgeries, radiotherapies, or procedures 
related to the studied disease (screening) 
­ Concomitant signs and symptoms linked to the studied disease 
­ Previous and concomitant treatments 


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Clinical examination and vital signs measurements 
­ Serum/urine pregnancy test (ß hCG) only for WOCBP 
­ Complete clinical examination (including examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological), height and body weight measurement and ECOG PS 
assessment 
­ Vital signs measurements including blood pressure (BP) measurements, heart rate (HR) and 
temperature, HR and BP measured by an automatic device in supine position after a 5-min 
rest 
Laboratory tests 
The laboratory assessments detailed in Table (8.2) 1 will be performed as indicated in 
sections 8.2.2 and 8.2.3. Additional tests could be repeated if clinically indicated. 
Table (8.2) 1 - Local Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Haematology 
Haematocrit, Haemoglobin, Red blood cells, WBC, Platelets, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Blasts in absolute value and in %) 
Total and B-
lymphocytes 
Total and B-lymphocyte count 
Biochemistry 
Albumin, Alkaline Phosphatase (ALP), ALT, AST, Bicarbonates, Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Total Calcium, Ionized Calcium, 
Magnesium, Phosphorus, Sodium, Potassium, Creatinine (including creatinine clearance), 
CK/CPK, Total Bilirubin, Total Cholesterol, LDL, HDL, Triglycerides, BUN or Urea, Uric 
Acid 
Amylase, Lipase, Glucose  
Cardiac 
markers 
BNP, CPK-MB, Troponin I or T* 
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 
International Normalized Ratio (INR), activated Partial Thromboplastin Time (aPTT)  
Thyroid 
T3 [free], T4 [free], TSH 
Hepatitis 
markers 
HbsAg, HbsAb, HbcAb, if HbsAg or HbcAb positive check viral load (HBV-DNA) at 
baseline, HCV RNA-PCR, HEV RNA-PCR 
Pregnancy 
Test 
When effective contraception is required, pregnancy testing is mandatory at inclusion 
(serum), on CxD1 predose of every cycle from Cycle 2 onwards (serum or urine) and at WV 
(serum) 
*The same subtype (either I or T) should be used throughout the study. If, for a given centre, both troponin I and 
T can be assessed, priority should be given to troponin I 
All samplings for biochemistry should be taken in fasting conditions, unless cholesterol, LDL, 
HDL, triglycerides and glucose are not measured (e.g. TLS monitoring). 
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. 


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Any laboratory abnormality that has a clinical impact on the patient, e.g. results in delay of 
study medication dosing, study discontinuation, requires treatment due to abnormal values, or 
is considered by the investigator to be medically important, must be reported as an AE, unless 
it is considered as a supporting lab to a clinical diagnosis already reported as an AE. If there is 
a question or concern, please call the Sponsor. All laboratory data will be analysed using NCI 
CTCAE grade criteria v5.0. 
During the course of the study, the results of laboratory tests should be available before the 
following S64315 administration and/or azacitidine CxD1 predose. 
Electrocardiograms (see section 8.2.5.1) will be assessed following the collection plan 
detailed in Table (8.2) 2. 
Table (8.2) 2 - Central ECGs collection plan 
Period 
Day 
Time 
ECG Type 
Inclusion 
ICF signature to LID1 
Anytime* 
12-Lead, triplicate 
LID1 
 
-13 
S64315 predose** 
-13 
S64315 EoI 
-13 
1h after S64315 EoI 
-13 
2h after S64315 EoI 
-13 
6h after S64315 EoI 
-12 
24h after S64315 EoI 
LID2 
 
-6 
S64315 predose** 
-6 
S64315 EoI 
-6 
1h after S64315 EoI 
-6 
2h after S64315 EoI 
-6 
6h after S64315 EoI 
-5 
24h after S64315 EoI 
Cycle 1 
 
1 
Azacitidine predose 
2 
S64315 predose*** 
2 
S64315 EoI 
2 
1h after S64315 EoI 
2 
2h after S64315 EoI 
2 
6h after S64315 EoI 
3 
24h after S64315 EoI 
9# 
S64315 predose** 
9# 
S64315 EoI 
9# 
1h after S64315 EoI 
9# 
2h after S64315 EoI 
9# 
6h after S64315 EoI 
10# 
24h after S64315 EoI 
16 
S64315 predose** 
16 
S64315 EoI 
23 
S64315 predose** 
23 
S64315 EoI 
Cycle 2 
2 
S64315 predose*** 
2 
S64315 EoI 
Cycle 3 and beyond 
2 
S64315 predose*** 


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Period 
Day 
Time 
ECG Type 
2 
S64315 EoI 
Withdrawal visit 
WV 
Anytime 
Unscheduled sample**** 
Anytime 
EoI: End of Infusion 
NOTE: A PK sampling is to be performed in conjunction with ECG whenever applicable (N/A 6h after S64315 
EoI) 
*to be collected within 7 days prior to inclusion and results available for inclusion 
**to be collected within 24 hours before S64315 infusion 
***to be collected after azacitidine administration on day of coadministration 
****A PK sample should be collected immediately following an ECG performed due to an unexpected cardiac 
signal (one for S64315 and one for azacitidine dosing purpose on days of coadministration; otherwise only 
one for S64315 dosing purpose) 
# or next S64315 infusion if Day 9 administration is not performed 
Echocardiography: LVEF parameter (see section 8.2.5.2) 
8.2.1. 
Screening period and inclusion visit 
Prior to the inclusion and after ICF signature, the clinical assessments will include: 
­ Medical, surgical and radiotherapy history 
­ Previous and concomitant treatments 
­ Complete physical examination (including examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological examination including sensory and motor evaluation 
functions) 
­ Clinical evaluation including vital signs (temperature, HR, BP), body weight, height, and 
ECOG PS within 7 days before the inclusion 
­ Laboratory tests: blood haematology with differential, blood biochemistry (fasted) blood 
coagulation, thyroid function, urinary analysis within 7 days before inclusion and available 
for inclusion and hepatitis markers within inclusion period 
­ Cardiac markers (limited to troponin only) 
­ Serum pregnancy test for female of childbearing potential within 7 days before inclusion and 
available for inclusion 
­ Cardiac function assessment performed by echocardiography or MUGA scan; GLS 
assessment will be recommended during echocardiography, whenever possible, as a means 
to follow left ventricular systolic dysfunction 
­ Chest X-Ray (CXR), a chest X-Ray performed prior to ICF signature but no more than 21 
days prior to the first day of IMP administration is acceptable 
- 
Triplicate ECGs (i.e. 3 ECGs within 10 min): see Table (8.2) 2 
8.2.2. 
During the treatment period 
S64315 LID period 
­ Clinical examination: 
 Vital signs (temperature, HR, BP): LID1 and LID2 predose*, LID1 and LID2 End of 
Infusion (EoI), 2h and 24h after LID1 and LID2 EoI 
 ECOG PS at LID1 predose* 


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­ Laboratory tests: 
 Blood haematology with differential and blood biochemistry (fasted): LID1 and LID2 
predose*, 24h and 48h after LID1 and LID2 EoI. A blood haematology sample should be 
obtained between LID1 and LID2 and between LID2 and C1D1 to ensure WBC are < 10 
G/L during the LID period 
 Blood biochemistry limited to AST, ALT and total bilirubin: 8h after LID1 and LID2 EoI  
 Cardiac markers (including troponin, CPK-MB and BNP): LID1 and LID2 predose*, 6h, 
24h, 48h and 72h after LID1 and LID2 EoI 
 TLS laboratory parameters monitoring (WBC, creatinine, phosphorus, calcium, 
potassium, uric acid, LDH): LID1 and LID2 predose*; 2h, 4h, 8h and 24h± 2h after LID1 
and LID2 EoI 
 Blood coagulation, thyroid function and urinary analysis at LID1 predose* 
*Predose exams to be performed within 3 days prior to LID1 or LID2 
­ Triplicate ECGs: see Table (8.2) 2 
Cycle 1 
­ Clinical examination: 
 Vital signs (temperature, HR, BP): 
 D1: azacitidine predose* 
 D2, D9, D16 and D23: S64315 predose*, S64315 EoI and 2h after S64315 EoI 
 ECOG PS on D1 azacitidine predose* 
 Body weight on D1 azacitidine predose* 
­ Laboratory tests: 
 Blood haematology with differential and blood biochemistry: 
 D1: azacitidine predose* 
 D2: S64315 predose* and EoI 
 D9, D16 and D23: S64315 predose* 
 Blood biochemistry limited to AST, ALT and total bilirubin: 8h, 24h and 72h after 
S64315 C1D2 EoI and 24h after C1D9 EoI 
 Blood coagulation, thyroid function and urinary analysis on D1 predose* 
 Cardiac markers (including troponin, CPK-MB and BNP)#: D1: azacitidine predose*, D2 
and D9: S64315 predose*, 6h, 24h, 48h and 72h after EoI, D16 and D23: S64315 
predose* 
#In case of any troponin increase observed after the two first S64315 infusions of cycle 
1, it will be recommended to assess cardiac markers at 48h and 72h after S64315 EoI, 
and after each subsequent infusion (before discharge and beyond, if needed), on a regular 
basis according to investigator’s judgment. 
 TLS laboratory parameters monitoring (WBC, creatinine, phosphorus, calcium, 
potassium, uric acid, LDH): 
 D1: predose*, 1h30 and 6h after azacitidine administration 
 D2: predose*, 2h, 4h, 8h, 24h±2h after S64315 EoI 
 beyond D2 (applicable for all patients with a risk of developing TLS according to the 
investigator’s judgment): prior to each S64315 infusion (predose) and 2h, 4h, 8h, 
24h±2h after each S64315 EoI 
*Predose exams to be performed within 24h prior to S64315 C1D2 and 3 days prior to any 
other IMP administration 
­ Triplicate ECGs: see Table (8.2) 2 
 


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If Day 9 administration is not performed, all scheduled assessments should be performed at the 
next S64315 infusion (2nd S64315 infusion in cycle 1). 
 
Cycle 2 and cycle 3 
­ Clinical examination:  
 Vital signs (temperature, HR, BP): D1 azacitidine predose*, D2 S64315 predose* and 
EoI, D9 S64315 predose*, D16 S64315 predose*, D23 S64315 predose* 
 ECOG PS on D1 azacitidine predose* 
 Body weight on D1 azacitidine predose* 
­ Laboratory tests: 
 Blood haematology with differential and blood biochemistry: D1 predose*, D2 predose*, 
D9 predose*, D16 predose*, D23 predose* 
 Blood coagulation, thyroid function and urinary analysis on D1 predose* 
 Cardiac markers (including troponin, CPK-MB and BNP) #: D1 predose*, D2 predose*, 
D9 predose*, D16 predose*, D23 predose*  
# in case of any troponin increase observed after the two first S64315 infusions of cycle 1, it 
will be recommended to assess cardiac markers at 48h and 72h after S64315 EoI, and after 
each subsequent infusion (before discharge and beyond, if needed), on a regular basis 
according to investigator’s judgment 
 TLS laboratory parameters monitoring (WBC, creatinine, phosphorus, calcium, 
potassium, uric acid, LDH), applicable for all patients with a risk of developing TLS 
according to investigator’s judgment, prior to each S64315 infusion; 2h, 4h, 8h, 24h ± 2h, 
after each S64315 EoI 
* Predose exams to be performed within 3 days prior any IMP administration 
­ Pregnancy test for women of childbearing potential (serum or urine) on D1 
­ Triplicate ECGs: see Table (8.2) 2 
­ Cardiac function assessment performed by echocardiography or MUGA scan on D1 predose 
within 2 days prior to the IMP administration 
Cycle 4 and beyond 
­ Clinical examination:  
 Vital signs (temperature, HR, BP) on D1 and D2 predose* 
 ECOG PS on D1 predose* 
 Body weight on D1 predose* 
­ Laboratory tests: 
 Blood haematology with differential and blood biochemistry: D1 predose*, D2 predose*, 
D9 predose*, D16 predose*, D23 predose* 
 Blood coagulation and urinary analysis on D1 predose* 
 Cardiac markers (including troponin, CPK-MB and BNP)#: D1 predose*, D2 predose*, 
D9 predose*, D16 predose*, D23 predose* 
# in case of any troponin increase observed after the two first S64315 infusions of cycle 1, 
it will be recommended to assess cardiac markers at 48h and 72h after S64315 EoI, and after 
each subsequent infusion (before discharge and beyond, if needed), on a regular basis 
according to investigator’s judgment 
 Thyroid function on D1 predose* of each cycle until cycle 6, then if no effects on the 
thyroid function is observed on D1 predose* every 4 cycles from cycle 6 onwards 
 TLS laboratory parameters monitoring (WBC, creatinine, phosphorus, calcium, 
potassium, uric acid, LDH), applicable for all patients with a risk of developing TLS 
according to investigator’s judgment 


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* Predose exams to be performed within 3 days prior to any IMP administration 
­ Pregnancy test for women of childbearing potential (serum or urine) on D1 
­ Triplicate ECGs: see Table (8.2) 2 
­ Cardiac function assessment performed by echocardiography or MUGA scan every 2 cycles; 
from cycle 4 onwards on D1 predose and within 2 days before azacitidine administration 
8.2.3. 
Withdrawal visit 
­ Clinical examination: vital signs (temperature, HR, BP), ECOG PS and body weight 
­ Laboratory tests: blood haematology with differential, blood biochemistry, blood 
coagulation and urinary analysis 
­ Pregnancy test for women of childbearing potential (serum) 
­ Triplicate ECGs: see Table (8.2) 2 
­ Cardiac function assessment performed by echocardiography or MUGA scan (only if the 
previous assessment was performed more than 3 weeks ago) 
8.2.4. 
Post-withdrawal follow-up 
After the withdrawal visit, a contact or telephone call will be done with the patients: 
­ every 3 months (±15 days) from the WV, up to 6 months, except in case of consent 
withdrawal for the dose escalation phase I part 
­ every 3 months (±15 days) from the WV, up to 12 months, except in case of consent 
withdrawal for the expansion phase II part 
The following information will be collected: 
­ the patient’s survival 
­ the date of first disease progression 
­ the first line of therapy administered after withdrawal and its starting date 
8.2.5. 
Cardiac safety 
8.2.5.1. 
Central ECG recording 
In order to monitor the potential of S64315 infusion in combination with azacitidine to delay 
cardiac repolarisation, serial triplicate 12-lead ECGs (i.e. 3 ECGs within 10 min) will be 
performed for the measurement of the QT and QTc interval (correction according to Fridericia’s 
formula). 12-lead ECG parameters with at least 3 to 5 QRS complexes for each lead will be 
evaluated by Core Reading Centre: HR, PR interval, QRS duration, QT interval, RR interval, 
corrected QT, using Fridericia’s formula. 
Three print-out ECGs will be produced with at least 6 complexes recorded for each. The ECG 
recordings will be centrally read by a CRO, specialised in cardiac monitoring. The CRO will 
provide a 12-lead digital recorder, will train and certify the centres in terms of equipment and 
will employ a trained independent cardiologist to read the ECGs. 
At each time point described in Table (8.2) 2, the triplicate 12-lead ECG will be obtained after 
resting for 10 min prior to the recordings and in supine position. Predose ECG should be 
collected: 
­ within 7 days prior to inclusion and results available for inclusion 
­ after azacitidine injection and before S64315 infusion on CxD2 (day of coadministration) 
­ with 24h prior to any other S64315 infusion 


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Detailed instructions on ECG recordings are provided in the ECG manual. 
In the event that an ECG abnormality is observed, additional examinations could be performed 
at the discretion of the investigator (e.g. a blood sample for ionogram (Na, K, Cl) in case of 
QTc prolongation). 
The management of the patient/the study treatment will be based on the local reading of the 
ECGs; all the ECGs will be sent by the site on a regular basis to the central reading CRO. The 
final analysis of the QTc values throughout the study will be based on the central reading 
analysis. 
At inclusion visit 
The mean QTc will be calculated for each triplicate ECG according to Fridericia’s formula. If 
the mean QTc is > 450 ms in men or > 470 ms in women, then 3 other ECGs (in 10 min) should 
be repeated 3 h later. The mean QTc will be recalculated. If the abnormality is confirmed, the 
patient will not be included. 
During the study 
Triplicate ECGs will be carried-out at the time points defined in Table (8.2) 2. The mean QTc 
will be calculated to detect a possible QTc prolongation. Toxicity grading of QTc interval 
prolongation is defined by the CTCAE v 5.0 as follows: 
 
Table (8.2.5.1) 1 - Toxicity grading of QTc interval prolongation is defined by the CTCAE (v 5.0) 
Grade 
Definition 
1 
QTc 450 - 480 ms 
2 
QTc 481 - 500 ms 
3 
QTc ≥ 501 ms on at least two separate ECGs 
4 
Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia 
In the event of prolongation of the QTc interval according to Fridericia’s formula, management 
of treatments will be performed as explained in the Table (8.12) 1. 
The recommendations described in the Table (8.12) 1 are not intended to supersede the clinical 
judgment of the investigator and the treating physician, who will determine the appropriate 
management for the patient. ECG abnormalities considered clinically significant by the 
investigator will be reported in the eCRF as adverse events. 
8.2.5.2. 
Echocardiography/ MUGA scan 
An echocardiography or a MUGA scan will be performed during the study to assess cardiac 
function. The same technique (either echocardiography or MUGA) should be used throughout 
the study for a given patient. 
At inclusion visit, if LVEF is < 50%, the patient is ineligible. 
During the study, the management of decrease in LVEF is based on the measured LVEF and 
LVEF change from baseline described in section 8.12. 
GLS assessment will be assessed during echocardiography, whenever possible (not mandatory), 
to follow left ventricular systolic dysfunction, at the time points already defined for 
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8.2.5.3. 
Cardiac marker follow-up 
In order to monitor a potential cardiac toxicity, a cardiac marker assessment, including troponin, 
CPK-MB and BNP, will be performed at predose, 6h, 24h, 48 and 72h after S64315 EoI on the 
days of LID1 (D-13) and LID2 (D-6), C1D2 and C1D9 and at each pre-dose assessments for 
the following visits.  
Either troponin I or T assessment can be used, but it should be ultra-sensitive, whenever 
possible. The same subtype (either I or T) should be used throughout the study. If, for a given 
centre, both troponin I and T can be assessed, priority should be given to troponin I. 
In case of troponin increase observed after any of the first two S64315 infusions during cycle 1 
(C1D2 or C1D9), it will be recommended to assess these cardiac markers at 48h and 72h 
S64315 EoI and after each subsequent S64315 infusions (before discharge and beyond, if 
needed) on a regular basis according to the investigator’s judgment. 
In case of troponin increase > 10xUNL or a troponin increase consistent with the diagnosis of 
a myocardial infarction (Grade 3), the patient should discontinue study treatment (see 
section 8.12). 
8.2.5.4. 
MRI assessment 
A cardiac MRI should be performed at the time of the event (as far as possible within 48 to 72h) 
in case of troponin increase > 10xULN or in case of troponin increase > ULN associated with 
clinical signs or LVEF decrease or ECG abnormality, to detect a potential acute structural effect 
related to S64315. Another cardiac MRI should be performed 5 or 6 weeks later, to detect any 
long-term damage related to S64315. 
In case of MRI abnormality in this context of troponin increase, the patient should discontinue 
study treatment (see section 8.12). 
8.2.5.5. 
24-hour Holter assessment 
A 24-hour Holter should be set-up in case of troponin increase > 10xULN (immediately once 
detected) or troponin > ULN associated with clinical signs or LVEF decrease or ECG 
abnormality to detect arrhythmia. Abnormalities considered clinically significant by the 
investigator and/or local cardiologist will be reported in the eCRF as adverse events. 
8.2.6. 
Hepatic safety 
Considering the results of the GLP toxicity studies showing some hepatotoxic effect of the drug, 
the hepatic safety will be closely monitored. An increase in serum liver enzymes should be 
followed by repeated 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 Grade 3 total bilirubin increase (> 3xULN) or isolated Grade 3 AST or ALT 
increase (> 5xULN), the patient should be weekly monitored, including LFT: albumin, ALT, 
AST, total bilirubin, fractionated if total bilirubin > 2.0xULN, ALP, fractionated if 
ALP > 2.0xULN, and GGT, or more frequently if clinically indicated, until values have 
resolved to baseline or stabilised over 4 weeks 
­ For AST or ALT > 3.0xULN combined with total bilirubin > 2.0xULN, repeat LFT as soon 
as possible, preferably within 48h from awareness of the abnormal results, then with weekly 
monitoring of LFT, or more frequently if clinically indicated, until AST, ALT, or bilirubin 
values have resolved to baseline or stabilised over 4 weeks 


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Clinically significant abnormalities should 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 
The recommendations towards the study according to the level and evolution of hepatic 
abnormalities are detailed in section 8.12. 
8.2.7. 
Monitoring of infections that may occur with neutropenia 
A possible co-toxicity on bone marrow and lymphoid organs, identified as primary target organs 
for both compounds in the toxicology studies, should be considered. Therefore, WBC count 
should be closely monitored, and caution should be exercised in assessing the possibility of 
infections in the patients receiving S64315 in combination with azacitidine. 
Early initiation of empirical broad-spectrum antibacterial antibiotics is recommended in the 
event of fever. If fever persists for 4 to 7 days, an antifungal treatment should also be 
considered. Investigators should employ these agents in compliance with best medical practices 
and institutional guidelines and standards. Before initiating these treatments, the list of non-
authorized treatments must be consulted. For quinolone agents, besides the possible DDI, the 
possible risk of prolongation of the QTc interval must be assessed (refer to section 6.3 and 
‘Guidance on use of co-medication for CL1-64315-004 clinical study’). 
The use of recombinant hemopoietic growth factors, specifically prohibited in Cycle 1, may be 
used beyond Cycle 1 at the discretion of the Investigator. 
8.2.8. 
Gastrointestinal disorders 
8.2.8.1. 
Nausea and vomiting management 
Considering the GLP toxicity studies and the preliminary clinical data with S64315 (as of 
September 5, 2019, 23 (60.5%) and 19 (50%) out of 38 patients treated in the S64315 single 
agent AML and MDS study experienced nausea and vomiting respectively), nausea/vomiting 
prophylaxis is strongly recommended before each S64315 infusion. 
Dexamethasone administration is mandatory at least 1h before S64315 infusion on the days of 
LID1 and LID2, and on C1D2. 
Based on international guideline (ASCO, 2011), this prophylaxis consists in a two-drug 
combination of palonosetron and dexamethasone, before each S64315 infusion, followed by 
dexamethasone maintenance for two days after each S64315 infusion. 
According to azacitidine E.U. SmPC, patients should be premedicated with anti-emetics for 
nausea and vomiting.  
The recommended prophylaxis is displayed in the Table (8.2.8.1) 1. 


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Table (8.2.8.1) 1 - Treatments schedule for nausea/vomiting prophylaxis 
LID1 and LID2 
Palonosetron 0.25 mg IV or 0.5 mg p.o.+ Dexamethasone 8 mg p.o. / IV 1h before each 
S64315 infusion, followed by dexamethasone 8 mg p.o. / IV during two days after each 
S64315 infusion, as required  
CxD1 
Metoclopramide IV before azacitidine administration 
CxD2 
Palonosetron 0.25 mg IV or 0.5 mg per os (p.o.) before azacitidine administration + 
Dexamethasone 8 mg p.o. / IV. 1h before S64315 infusion 
CxD3 
Dexamethasone 8 mg p.o. / IV. as required 
CxD4 
Dexamethasone 8 mg p.o. / IV. as required 
CxD9 
CxD16 
CxD23 
Palonosetron 0.25 mg IV or 0.5 mg p.o.+ Dexamethasone 8 mg p.o. / IV before each 
S64315 infusion, followed by dexamethasone 8 mg p.o. / IV during two days after each 
S64315 infusion, as required  
If palonosetron is not available, clinicians may substitute with a first-generation 5-HT3 
serotonin receptor antagonist (i.e. granisetron/ dolasetron/ tropisetron, to be used with caution 
according to ‘Guidance on use of co-medication for CL1-64315-004 clinical study’). 
Limited evidence also supports adding aprepitant to the combination, if the above combination 
does not provide sufficient nausea/vomiting control. 
As a reminder, ondansetron is prohibited along the study due to the risk of QTcF prolongation 
(see ‘Guidance on use of co-medication for CL1-64315-004 clinical study’). 
For patients who experience nausea and/or vomiting despite optimal prophylaxis, clinicians 
should re-evaluate emetic risk, disease status, concurrent illnesses, and medications and 
consider adding lorazepam or alprazolam or adding a dopamine antagonist to the regimen.  
Please refer to sections 6.3.1 and 6.3.2 for more information about the prohibited medications 
and the medications to be used with caution during IMP treatment. 
8.2.8.2. 
Diarrhoea management 
Considering the GLP toxicity studies and the preliminary clinical data with S64315 (17/38, 
44.7%) patients treated in the S64315 monotherapy AML and MDS study experienced 
diarrhoea), diarrhoea should be closely monitored. 
The patient should be instructed to contact the physician/other study personnel in case of severe 
diarrhoea. 
In case of diarrhoea, management and treatment approaches should be implemented according 
to routine practice and applicable guidelines. In case no guideline is available, investigators 
should refer to ESMO clinical practice guidelines for diarrhoea in adult cancer patients.  
Guidance for diarrhoea management (ESMO, 2018) is summarised in Appendix 7. 
8.2.9. 
Tumour Lysis Syndrome management 
Tumour Lysis Syndrome (TLS) prophylaxis is required during the administration of S64315 in 
combination with azacitidine for patients with active disease, in case of intra-patient dose 
escalation to a new assigned dose(s) and in case of readministration after one or both IMPs 
interruption ≥ 28 days. 
Even if only patients with low/intermediate risk of TLS are included, TLS prophylaxis for 
intermediary risk should be implemented for any patient considering the expected overlapping 
toxicity of the combination. TLS management will be based on institutional guidelines and 
published criteria (Cairo, 2010) and on the recommendations described below. 


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Hydration 
Adequate hydration should be ensured for all patients according to routine clinical practice and 
international guidelines (Cairo, 2010). 
In order to prevent the risk of TLS, hydration will be made mandatory during the LID period 
and during the two first infusions of S64315 at the full tested dose (LID1, LID2, C1D2 and 
C1D9). Patients should be encouraged to drink up to 1.5 to 2.0 L of water daily starting the day 
before the S64315 infusion, and 24 hours after. Intravenous fluids at 50cc/hour or higher are 
recommended to be administered for at least 12 hours prior to the S64315 infusion, then IV 
fluid should be continued according to the investigator’s judgement. The rate of IV fluids 
should be adjusted per clinical judgment. 
Anti-hyperuricaemic agents 
Allopurinol is recommended for patients with active disease throughout the study. Patients who 
develop laboratory TLS should receive rasburicase unless clinically contraindicated (Cairo, 
2010). 
Laboratory assessments (see section 8.2.2). 
Before and following S64315 infusions during the LID period (LID1 on D-13 and LID2 on 
D-6): 
WBC, serum uric acid, serum calcium, serum phosphorus, serum potassium, serum creatinine 
and LDH must be monitored at the following time points: 
­ Prior to S64315 administration (LID1 and LID2 predose) 
­ 2h, 4h and 8h after S64315 EoI (LID1 and LID2) 
­ 24h (± 2h) after S64315 EoI (LID1 and LID2) 
Before and following the first azacitidine administration (C1D1) and first S64315 infusion 
(C1D2) of cycle 1: 
WBC, serum uric acid, serum calcium, serum phosphorus, serum potassium, serum creatinine 
and LDH must be monitored at the following time points: 
­ Prior to azacitidine first injection (C1D1 predose) 
­ 1h30 and 6h after azacitidine first injection (C1D1) 
­ After azacitidine second injection and prior to first S64315 infusion (C1D2) 
­ 2h, 4h and 8h after S64315 EoI (i.e. C1D2) 
­ 24h (± 2h) after S64315 EoI (i.e. C1D3) 
Beyond the first infusion of S64315 (applicable for all patients with a risk of developing TLS 
according to the investigator’s judgment): 
WBC, serum uric acid, serum calcium, serum phosphorus, serum potassium, serum creatinine 
and LDH must be monitored at the following time points: 
­ Prior to each S64315 infusion (i.e. CxD9, CxD16, CxD23 predose) 
­ 2h, 4h and 8h after each S64315 EoI (i.e. CxD9, CxD16, CxD23) 
­ 24h (± 2h) after each S64315 EoI (i.e. CxD10, CxD17, CxD24) 
Electrolyte abnormalities should be corrected promptly. 
Hospitalization 
To enable close in-patient TLS monitoring and management, patients must be hospitalized: 
­ at least 12h before the day of LID1 and for at least 24h after LID1 
­ at least 12h before the day of LID2 and for at least 24h after LID2 


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­ at least 12h before C1D1 and for at least 24h after C1D2 S64315 infusion (including C1D1, 
C1D2 and C1D3) 
If a biological or clinical TLS develops, additional measures should be implemented according 
to guidelines (Howard, 2011), including dialysis if clinically indicated. 
In case of intra-patient dose escalation, the patient will be hospitalized for at least 3 days. 
8.2.10. Infusion Related Reaction management 
As the risk of Infusion Related Reaction (IRR) is not yet well characterized, it is challenging at 
this stage to propose a standardized prophylactic treatment before the first S64315 infusions. 
However, before S64315 infusion during LID period, cycle 1, and during following cycles at 
the investigator’s discretion according to conventional practices, patients should receive the 
following: 
­ Hydration: already planned in the frame of TLS prophylaxis (see section 8.2.9) 
­ Corticoids (dexamethasone): already planned in the frame of nausea/vomiting prevention 
(see section 8.2.8.1) 
­ Additionally, according to investigator’s opinion, anti H1 and/or anti H2 could be 
administered before S64315 infusion 
­ Patient’s risk factors to develop IRR such as age-related factors, concomitant diseases (e.g. 
chronic respiratory diseases, cardiovascular diseases, severe atopic disease) and concomitant 
medications (e.g. β-adrenergic blockers and angiotensin-converting enzyme inhibitors), 
should be assessed before treating the patient 
In addition, patient vital signs (BP, HR, temperature) should be monitored as follows: 
­ during the LID period for each S64315 infusion: EoI, at least 2h and 24h after EoI (LID1 
and LID2) 
­ during Cycle 1 for each S64315 infusion: EoI and at least 2h after EoI (C1D2, C1D9, C1D16, 
C1D23) 
In case of occurrence, IRR management will be performed according to ESMO guidelines 
(ESMO, 2017) as presented in Figure (8.2.10) 1 or according to local practice guidelines. If the 
patient experiences an IRR of grade 1 or 2, the infusion rate should be immediately decreased 
by 50% of the initial rate without exceeding 3 hours of total infusion time or infusion 
immediately stopped according to the investigator judgment and based on the severity of 
symptoms. The patient’s vital signs (eg: blood pressure, heart rate, respiration, temperature) 
should be monitored every 15 minutes until the event has resolved. 
To allow better characterization of IRR, it is recommended to perform blood samplings for the 
measurement of tryptase levels optimally 15 min to 3h after the onset of the IRR. A new sample 
should be obtained from 48h to 72h after the onset of the event (baseline value).  
With regards to rechallenge, the following guidelines should be considered: 
­ Grade 1 IRR: adequate prophylaxis should be implemented before each subsequent S64315 
infusion 
­ Grade 2 IRR: adequate prophylaxis should be implemented before each subsequent S64315 
infusion 


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­ Grade 3 IRR: 
 If serious adverse event: no rechallenge is permitted 
 If non-serious adverse event: rechallenge is permitted according to the expected benefit 
risk ratio and provided that an adequate prophylaxis is implemented before each 
subsequent S64315 infusion, and upon sponsor’s approval 
­ Grade 4 IRR: rechallenge is not permitted. 
 
Figure (8.2.10) 1 - Management of IRR to systemic anticancer therapy ESMO clinical practice guidelines 
 
8.2.11. Specific COVID-19 situation 
In case of highly suspected COVID-19 infection (based on typical symptoms or typical chest 
CT scan images) or confirmed COVID-19 infection (based on positive COVID-19 biological 
testing), the study treatment(s) should be immediately interrupted.  
The study treatment(s) could be restrated if patient is asymptomatic for at least 15 days after 
the diagnosis or with a negative test. 
8.3. Definition of adverse events 
An adverse event is defined as any untoward medical occurrence in a patient participating in a 
clinical study, whether or not there is a causal relationship with the IMPs and/or experimental 
procedures, occurring or detected from the date the patient signs the information and consent 
form, irrespective of the period of the study. 


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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, etc.) 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 patient 
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 patient’s diary or safety evaluation 
scale) 
 
Of note: 
­ Any hospitalisation for administration of anti-tumour 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 patient) or routine check-up should 
not be considered as an adverse event and should not be reported in the eCRF. 
­ The following procedures, whether planned before the study or not, whether leading to a 
hospitalisation or not, should not be reported in the eCRF and kept in the source data 
(or patient file): 
 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) 
 prophylactic procedures (e.g. sterilisation, wisdom teeth removal) 
 comfort procedures (e.g. cosmetic surgery) 
 control procedures of a pre-existing condition without aggravation (e.g. colonoscopy to 
control the remission of colon cancer) 
8.4. Definition of Serious adverse events 
A Serious Adverse Event (SAE) is 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 patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were more 
severe.  
(2) Any event that might not be immediately life-threatening or result in death or hospitalisation but might 
jeopardise the patient 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. 


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(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the patient 
to lead a normal life, in other words leads to a persistent or permanent significant change, deterioration, 
injury or perturbation of the patient'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. For instance, if the study protocol requires a unique 
daily administration, one administration of twice the dose or two administrations of the full 
tested dose on the same day should be both considered as overdoses. 
8.6. Definition of Adverse event of special interest 
Not applicable 
8.7. Definition of Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. without delay and within 24h at the latest) to the 
sponsor if it is: 
­ a SAE 
­ an overdose of the IMP even if asymptomatic 
­ any intake of the IMP by a person around the patient 
­ 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 
intensity of the event as well as the cause-effect relationship between an adverse event and 
the IMPs. This evaluation must be assessed by the investigator and reported in the AE form. In 
addition, the sponsor will be responsible for the evaluation the expectedness of the event (see 
section 8.10). 
The Seriousness should be evaluated according to international guidance (see definition in 
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 
­ Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL1 
 
1 Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 


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­ 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 causal relationship to the IMPs, to the experimental procedures or to disease progression 
must be assessed when reporting the AE in the AE form. Cases ticked ‘related’ by the 
investigator or judged by the sponsor as having a reasonable suspected causal relationship to 
the IMPs (AE linked to the mechanism of action of the test drug, etc.), will be considered as 
suspected Adverse Drug Reaction. In general, if a relationship between AE and drug 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, and after the signature of the ICF, for event associated 
with any procedure/condition required by the study protocol: procedure (BMA, blood 
samples, MRI, etc.), change or withdrawal of previous/concomitant treatment relating to the 
conditions of the protocol 
­ at any time after the first intake of the IMP up to the patient’s last study visit for all events 
­ after the patient’s last study visit: 
 up to 30 calendar days after the patient's last study visit for all ERINs, regardless of the 
supposed role of the research (IMP or experimental procedure) 
 irrespective of the time of onset after the end of the study for all SAEs related to the 
research (IMP or experimental procedure) 
Of note, events occurring between the signature of the ICF 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 or symptoms 
related to the studied disease in the dedicated eCRF form. Fatal event, related or not to the 
research, occurring between ICF signature and before first IMP administration, must be 
reported on AE form.  
 
 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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All other AEs 
 
 
 
 
 
 
 to be reported 
as Medical 
history 
OR 
 
Signs & 
symptoms 
related to the 
studied disease  
 
 
 
 
 
 
 
 
All fatal events and 
AEs associated with: 
A procedure scheduled in the 
study protocol, 
A change or withdrawal of 
previous / concomitant 
treatment related to the 
conditions of the protocol, 
A product other than the IMPs, 
taken as part of the protocol. 
 
All AEs 
 
All ERINs 
 
All SAEs 
related to 
the research 
(IMPs, 
experimental 
procedure) 
 to be reported 
as Adverse 
Event 
 
 
 
 
  
  
 
Signing of the  
consent form  
1st administration  
of IMP 
 
Patient's last 
study visit  
30 calendar days 
after the patient's 
last study visit 
 
 
 
 
 
 
 
 
 
 
 
8.9.2. 
Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
­ Note in the patient's medical file the date on which he/she learned of the event (at a follow-
up visit or a telephone contact with the patient 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 IRB/IEC, 
in accordance with local regulations 
Moreover, the investigator must report to the sponsor and/or to the IRB/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 test drug or that would be sufficient to 
consider changes in the test drug administration or in the overall conduct of the clinical 
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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-test drug assessments should be appended for 
comparison with the results obtained under test drug, 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 patient 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 the ‘Adverse event’ page previously created for the event. 
If the adverse event has not resolved at the patient's final visit in the study, the patient must be 
followed up suitably and any information on the outcome of the event will be noted on the 
‘Adverse Event’ page previously created for the event. An adverse event ongoing at the time of 
a participant's death is considered to be Not Recovered. 
If the patient’s follow-up is not done by the investigator him/herself (hospitalisation, followed 
by a specialist or the patient's general practitioner, etc.), the investigator will do everything to 
establish/maintain contact with the person/department in charge of the patient’s follow-up. 
8.9.2.3. 
Special situations (pregnancy, overdoses, intake of IMP by a person around the 
patient) 
Pregnancy 
If a female patient in the study becomes pregnant, the investigator must: 
­ stop immediately the IMPs 
­ report it on an ‘Adverse Event’ page as well as on the specific paper pregnancy form (1st age) 
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 patient becomes pregnant during the course of the study, the pregnancy should 
not be reported in the eCRF. 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 
­ 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: 
 dose details (number of units, duration, etc.) and, if multiple overdose, details regarding 
other medicinal products or substance 
 context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental (error 
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 related signs and symptoms (‘No related adverse events’ to be reported otherwise) 
 outcome 
­ In so far as possible, an additional PK blood sampling should be collected for assay of the 
taken IMP 
Intake of IMP by a person around the patient 
This event should not be reported in the eCRF. 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 eCRF 
Adverse events must be documented on the eCRF ‘Adverse Event’ page. 
In case of chronic disease: 
­ if the disease is known when the patient 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 
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 patient's medical file as well as 
the eCRF ‘Adverse Event’ page according to the general instructions available in the eCRF, 
without waiting for the results of the clinical outcome or of additional investigations. When 
data is 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 IRB/IEC, in 
accordance with local regulations 
If an adverse event initially non-serious worsens and becomes a SAE, this must be reported 
immediately on the eCRF ‘Adverse event’ page. 
In case the eCRF is unavailable when the investigator was informed of the ERIN, he/she should: 
­ Immediately fill in a paper ‘Adverse event’ page 
 For serious event on a paper ‘Adverse event – Initial information’ page 
 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 
(01.55.72.60.00 for a call from France, or +33.1.55.72.60.00 for a call from outside France, 
and/or the specific phone line as specified in the instructions provided to each centre) 
­ As soon as the eCRF becomes available, enter this information in the eCRF ‘Adverse Event’ 
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8.10. Responsibilities of the sponsor 
In accordance with international guidance, 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 
SAEs, 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 (CSR). 
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 IMPs. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data and any new safety finding likely to affect the benefit /risk balance of 
the product, required in ICH Good Clinical Practice guidelines and local regulations, to the 
appropriate Authorities, to all the investigators involved and to the patients involved, through 
the investigators, as mentioned in section 13.4. 
The concerned Authorities will be notified as soon as possible by the sponsor of the DSMB 
recommendations if any, where relevant for the safety of patients (i.e. modification or 
termination of the study). 
8.11. Responsibilities of Data Safety and Monitoring Board 
Taken into account the innovative character of such a combination, the limited data from animal 
studies, the potential important safety risks associated with the administration of both IMPs, the 
vulnerability of the treated population, a DSMB will be set-up to review periodically the 
patients’ safety and efficacy data throughout the conduct of the study in order to ensure that the 
patients’ potential benefit is not compromised by safety concerns. 
In accordance with the DSMB charter and the rules for DSMB functioning, the DSMB is an 
independent group of experts who provides expertise and recommendations to the Sponsor. 
Their primary responsibility is to review safety and efficacy data in the light of the benefit-risk 
ratio on a regular basis and after the last patient of each cohort has completed the first cycle of 
treatment. After each meeting they will provide written recommendations to the International 
Coordinator/Investigators and the Sponsor regarding the progress and conduct of the study 
(continuation, modification or termination). Indeed, the DSMB can recommend escalating, de-
escalating the doses or extending a given cohort to additional patients according to the adopted 
study design. The DSMB could also give recommendations on the possible modification of the 
study protocol based on the review of the safety and efficacy data and suspend or early terminate 
the study in case of serious concerns about patient safety. The DSMB members will ensure their 
availability in case of any required extraordinary meeting. 
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8.12. Management of treatment dose adaptations due to toxicities 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatments. 
Dose modifications recommendations for S64315 are summarised in Table (8.12) 1.  
A patient must discontinue treatment with S64315 if, after treatment is resumed at a lower dose, 
the toxicity recurs with the same or worse severity, unless in the opinion of the investigator it 
is in the patient’s best interest to continue S64315, and upon documented agreement with the 
Sponsor. 
For each patient, once a dose reduction has occurred, the dose may not be re-escalated during 
the subsequent cycles unless in the opinion of the investigator it is in the patient’s best interest 
to continue S64315, and upon documented agreement with the Sponsor. 
When a patient meets the criteria for S64315 discontinuation described in the table, he/she must 
discontinue both IMPs. 
Dose modifications for azacitidine must be done according to azacitidine E.U. SmPC (see 
Table (8.12) 2). 
These dose changes must be recorded in the eCRF. 


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Table (8.12) 1 - Criteria for interruption and re-initiation of S64315 
Recommended dose modifications for S64315 
Worst toxicity 
CTCAE Gradea (unless otherwise specified) 
During a cycle of therapy 
Investigations (Renal)  
Serum creatinine 
Grade 2 (> 1.5 – 3 x ULN or > 1.5 – 3 x baseline) 
Omit dose until resolved to Grade ≤ 1 or baseline, then: 
- 
If resolved in ≤ 14 days, then maintain dose level 
- 
If resolved in > 14 days, then ↓ 1 dose level 
Grade 3 (> 3 – 6 x ULN or > 3 x baseline) 
Omit dose until resolved to Grade ≤ 1 or baseline, then ↓ 1 dose level 
Grade 4 (> 6 x ULN) 
Discontinue patient from test drug treatment 
Note: If intercurrent illness, e.g. dehydration due to diarrhoea or febrile infections, leads to prerenal insufficiency, this should not be considered drug related and the criterion 
for dose modification not fulfilled 
Investigations (Hepatic) 
Isolated Total Bilirubin elevationb 
Grade 2 (> 1.5 - 3.0 x ULN if baseline was normal, >1.5 
- 3.0 x baseline if baseline was abnormal)* 
Omit dose until resolved to Grade ≤ 1, then: 
- 
If resolved in ≤ 14 days, maintain dose  
- 
If resolved in > 14 days, ↓ 1 dose level  
Grade 3 (> 3.0 - 10.0 x ULN) 
Omit dose until resolved to Grade ≤ 1, then:  
- If resolved in ≤ 14 days, ↓ 1 dose level 
- If resolved in > 14 days, discontinue patient from test drug treatment 
The patient should be weekly monitored (including Liver Function Tests (LFT)f), or more frequently if clinically 
indicated, until total bilirubin has resolved to baseline or stabilised over 4 weeks 
Grade 4 (> 10.0 x ULN) 
Discontinue patient from test drug treatment 
The patient should be weekly monitored (including LFT), or more frequently if clinically indicated, until total 
bilirubin has resolved to baseline or stabilised over 4 weeks 
Isolated AST or ALT elevation 
AST or ALT > 3.0 – 5 x ULN 
Omit dose S64315 until resolved to ≤ 3 x ULN, then maintain dose 
Grade 3 (> 5.0 - 20.0 x ULN if baseline was 
normal; >5.0 - 20.0 x baseline if baseline was abnormal)  
Omit dose until resolved to ≤ 3 x ULN, then 
- 
If resolved in ≤ 14 days, maintain dose  
- If resolved in > 14 days, ↓ 1 dose level. 
Grade 4 (> 20.0 x ULN if baseline was normal; >20.0 
x baseline if baseline was abnormal) 
Discontinue patient from test drug treatment 


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Combinedc elevations of AST or ALT and total bilirubine 
AST or ALT > 3.0 x ULN combined with total 
bilirubin > 2.0 x ULN and confirmed Hy’s law cases 
according to FDA guidance 
- 
For patients with normal baseline ALT or AST or total bilirubin value 
If AST or ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN without evidence of cholestasisd: 
- 
Permanently discontinue patient from test drug treatment For patients with elevated baseline AST or ALT or 
 
total bilirubin value 
If [AST or ALT > 2.0 x baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, combined 
with [total bilirubin > 2.0 x baseline AND > 2.0 x ULN: 
- Permanently discontinue patient from test drug treatment. 
Repeat LFTf as soon as possible, perform liver imaging to assess biliary tract or liver disease (if possible), 
preferably within 48h from awareness of the abnormal results, then with weekly monitoring of LFTf, or more 
frequently if clinically indicated, until AST, ALT or bilirubin has resolved to baseline or stabilised over 4 weeks 
Investigation (Pancreatic) 
Amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
May maintain dose level 
> 1.5 - 2.0 x ULN 
May maintain dose level 
> 2.0 - 5.0 x ULN and asymptomatic  
Omit dose until resolved to Grade ≤ 1 or baseline then: 
- 
If resolved in ≤ 14 days, maintain dose level 
- 
If resolved in > 14 days, ↓ 1 dose level 
Grade 3 (> 2.0 - 5.0 x ULN with signs or symptoms 
or >5.0 x ULN and asymptomatic) 
Discontinue patient from test drug treatment 
Grade 4 (> 5.0 x ULN and with signs or symptoms) 
Discontinue patient from test drug treatment 
Note: A CT scan to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any Grade ≥ 3 amylase and/or lipase, or as clinically 
indicated 
Investigation (Metabolic) 
Creatine (phospho)kinase elevation 
Grade 3 
Omit dose until resolved to Grade ≤ 2, then: 
- 
If resolved in ≤ 14 days, maintain dose level 
- If resolved in > 14 days, ↓ 1 dose level 
Grade 4 
Omit dose until resolved to Grade ≤ 2, then: 
- 
If resolved in ≤ 14 days, then ↓ 1 dose level 
- If resolved in > 14 days, then discontinue patient from test drug treatment  


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Gastro intestinal 
Pancreatitis 
Grade ≥ 3 
Discontinue patient from test drug treatment 
Diarrhoea 
Grade 1 and 2g 
Maintain dose level, treat the patient per institutional diarrhoea management protocol 
Grade 3 
Omit dose until resolved to Grade ≤ 1, treat the patient per institutional diarrhoea management protocol, then: 
­ If resolved in ≤ 5 days, maintain dose level 
­ If resolved in > 5 days despite the use of optimal anti-diarrhoea therapy, ↓ 1 dose level 
Grade 4 
Discontinue patient from test drug treatment. 
Grade ≥ 3 Vomiting 
Maintain dose level, if not resolved to Grade ≤ 2 within 48h after start of optimal anti-emetic therapy, then omit 
dose until resolved to Grade ≤ 2, and then ↓ 1 dose level 
Metabolism and nutrition disorders 
Electrolyte abnormalities (if clinically significant) 
Grade 3 
Omit dose until resolved to Grade ≤ 1, then: 
- 
If resolved in ≤ 7 days, maintain dose level 
- If resolved in > 7 days, ↓ 1 dose level 
Grade 4 
Discontinue patient from test drug treatment 
Skin and subcutaneous tissue disorders 
Rash /photosensitivity 
Grade 1 
Maintain dose level 
Consider initiating appropriate skin toxicity therapy (e.g. antihistamines and topical corticosteroids) as per local 
institutional guidelines 
Consider skin biopsy for evaluation 
Grade 2 
Maintain dose level but initiate/intensify appropriate skin toxicity therapy (e.g. antihistamines, topical 
corticosteroids and low-dose systemic corticosteroids) as per local institutional guidelines and monitor closely 
Consider skin biopsy for evaluation 
Grade 3, despite skin toxicity therapy 
Omit dose and reassess the patient weekly until resolved to Grade ≤ 1, then: 
- If resolved in ≤ 14 days, ↓ 1 dose level 
- 
If resolved in > 14 days, discontinue patient form test drug treatment  
Consider referral to dermatologist and manage rash per dermatologist’s recommendations 
Consider skin biopsy for evaluation 


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Grade 4, despite skin toxicity therapy 
Discontinue patient from study treatment 
Consider referral to dermatologist and manage rash per dermatologist’s recommendations 
Consider skin biopsy for evaluation 
Cardiac disorders 
QTcF Prolongation 
QTcF interval ≥ 481ms or increase of > 60 ms from 
baseline on at least two separate ECG 
Omit S64315 dose, correct the possible electrolytes abnormalities (e.g. potassium, magnesium, etc.) and perform 
frequent ECGs* until resolves to Grade ≤ 1, then: 
- If resolved in ≤ 14 days, ↓ 1 dose level. Triplicate ECGs must be monitored on D1 of each cycle throughout 
the study 
- If resolved in > 14 days, discontinue patient from test drug treatment 
*Perform at least weekly ECGs until 2 weeks following resolution of the QTc prolongation 
LVEF Decrease 
Asymptomatic, absolute decrease in LVEF of 10% or 
greater from baseline and LVEF <50% 
Omit dose, obtain consultation with a cardiologist, and repeat cardiac imaging after 4 weeks 
- If improved to ≤ 10% from baseline and ≥ 50% within 4 weeks, then ↓ 1 dose level. Monitor LVEF on D1 of 
each subsequent cycle for at least 3 cycles; if no recurrence of LVEF decline and if agreed by the cardiologist, 
the frequency may then be decreased to every other cycle. 
- If not improved to ≤ 10% from baseline and ≥ 50% within 4 weeks, then discontinue patient from test drug 
treatment 
Absolute decrease in LVEF of 20% or greater from 
baseline and LVEF < 40% OR Symptomatic 
congestive heart failure 
Discontinue patient from test drug treatment and obtain consultation with a cardiologist 
NOTE: Upon discontinuation due to LVEF decrease, closely monitor LVEF until resolution. The same cardiac imaging modality (i.e. transthoracic echocardiography (TTE) 
or MUGA scan) used at baseline is to be used for all subsequent assessments 
Cardiac MRI abnormality 
In case of cardiac MRI abnormality clinically significant according to the cardiologist (e.g. compatible with 
ischemia or left ventricular dysfunction), in a context of troponin elevation, discontinue patient from study drug 
treatments 
Cardiac biomarkers 
Grade 1 troponin I or T elevation  
Omit dose, evaluate and treat patient per institutional guidelines. Follow Troponin I/T to resolution per institutional 
guidelines 
­ If no evidence of LVEF decrease from baseline of 10% or greater on TTE or MUGA* and Troponin I/T resolves 
to normal in ≤ 7 days, then maintain dose level 
­ If no evidence of LVEF decrease from baseline of 10% or greater on TTE or MUGA* and Troponin I/T resolves 
to normal in > 7 days, then ↓ 1 dose level. Consult with a cardiologist prior to re-initiating test drug 
­ If evidence of LVEF decrease from baseline of 10% or greater on TTE or MUGA, follow guidelines for LVEF 
decrease 


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*exams to be performed once per cycle or according to physician decision 
A clear investigation is required in case of isolated increase in troponin in order to consider the possible 
confounding factors before considering the abnormality as related to the test drug 
Troponin I or T elevation > ULN associated with clinical 
signs or LVEF decrease or ECG abnormality 
A cardiac MRI should be performed at the time of the event (as far as possible within 48h to 72h) and 5 to 6 weeks 
later, for functional cardiac assessment 
A 24-h Holter should be performed at the time of the event 
Troponin I or T elevation > 10 x ULN or troponin 
increase consistent with the diagnosis of a myocardial 
infarction (Grade 3) 
Discontinue the patient from test drug treatments 
A cardiac MRI should be performed at the time of the event (as far as possible within 48h to 72h) and 5 or 6 weeks 
later, for functional cardiac assessment  
A 24-hour Holter should be performed at the time of the event 
Eye Disorders (Results and images of ophthalmic examinations should be made available upon request) 
Other ocular/visual toxicity 
Grade 1 or 2 
Maintain dose level and increase ophthalmic monitoring frequency to at least every 14 days 
Refer the patient to an ophthalmologist within one week for evaluation 
Grade 3 
Omit dose until resolved to Grade ≤ 1, and increase ophthalmic monitoring frequency to at least once a week, and 
refer the patient to an ophthalmologist within one week for further evaluation, then: 
­ If resolved in ≤ 14 days, ↓ 1 dose level 
­ If resolved in > 14 days, discontinue patient from test drug treatment 
Grade 4 
Discontinue test drug treatment and refer the patient to an ophthalmologist for monitoring 
Haematological abnormalities (myelosuppression) 
Neutropenia and thrombocytopenia Grade 4 
If bone marrow clearance, omit dose and/or interrupt azacitidine until count recovery: 
­ If resolved in < 28 days, then maintain the dose level 
­ If resolved in > 28 days, then consider discontinuing patients from study unless the patient has evidence of 
clinical benefit and in discussion with the Sponsor a decision is made to continue therapy at a lower dose 
Other AEs 
Grade 3 
If Grade 3 (except those correctable within 7 days and deemed by the investigator to be not clinically important), 
hold treatment until resolved to Grade ≤ 1 or baseline, then: 
­ If resolved in ≤ 14 days, ↓ 1 dose level 
­ If resolved in > 14 days, discontinue patient from test drug treatment 
Grade 4 
Discontinue test drug treatment 
NOTE In some particular cases, a patient with a Grade 3 or Grade 4 AE may resume treatment at the lower dose level if in the opinion of the Investigator and after 
discussion with the Sponsor, the event is not life-threatening, and the patient can be managed and monitored for recurrence of the AE. 
In case of TLS Grade 3 or 4, the dose adaptation of the study drugs will be discussed between the sponsor and the investigator according to the patient's benefit/risk 
assessment. 


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All dose modifications should be based on the worst preceding toxicity. 
Patients may receive supportive care (e.g. packed red blood cells) as per local institutional guidelines. 
a Common Toxicity Criteria for Adverse Events (CTCAE v5.0) 
b If Grade 3 or 4 hyper-bilirubinaemia is due to the indirect (non-conjugated) component only, and haemolysis as the aetiology has been ruled out as per institutional guidelines 
(e.g. review of peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the investigator 
c ‘Combined’ defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold 
d ‘Cholestasis’ defined as: ALP elevation [> 2 x ULN and R value < 2] in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes the relative pattern of ALT and/or ALP elevation 
is due to cholestatic or hepatocellular liver injury)  
e If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, follow the instructions for isolated elevation of total bilirubin and isolated 
elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed for one 
parameter and discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that allow treatment re-initiation, restart the 
treatment either at the same dose or at one dose lower if a criterion for dose reduction is met. 
f LFT include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), ALP (fractionated if ALP > 2.0 x ULN) and GGT. For isolated elevations of 
any grade of ALP and/or GGT, maintain dose level. 
g Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhoea. 
* Note: Patients enrolled with Gilbert’s syndrome and elevated baseline bilirubin between > 1.5 x ULN and ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN can continue 
treatment. 


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Table (8.12) 2 - Criteria for interruption and re-initiation of azacitidine 
(see E.U. azacitidine SmPC) 
Dose adjustment due to haematological toxicity 
Haematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets ≤ 50.0 x 
109/L and/or absolute neutrophil count (ANC) ≤ 1 x 109/L. 
Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at least half 
of the difference of nadir and the baseline count plus the nadir count (i.e. blood count at recovery ≥ nadir count 
+ (0.5 x [baseline count – nadir count]). 
Patients without reduced baseline blood counts (i.e. WBC ≥ 3.0 x 109/L and ANC ≥ 1.5 x 109/L, and 
platelets ≥ 75.0 x 109/L) prior to the first treatment 
If haematological toxicity is observed following azacitidine treatment, the next cycle of the therapy should be 
delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose 
adjustment is necessary. However, if recovery has not been achieved within 14 days, the dose should be reduced 
according to the following table. Following dose modifications, the cycle duration should return to 28 days. 
 
Nadir counts 
% Dose in the next cycle, if recovery* is not 
achieved within 14 days 
ANC (x 109/L) 
Platelets (x 109/L) 
 
≤ 1.0 
≤ 50.0 
50% 
> 1.0 
> 50.0 
100% 
*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 
Patients with reduced baseline blood counts (i.e. WBC < 3.0 x 109/L or ANC < 1.5 x 109/L or platelets 
< 75.0 x 109/L) prior to the first treatment 
Following azacitidine treatment, if the decrease in WBC or ANC or platelets from that prior to treatment is 
≤ 50%, or greater than 50% but with an improvement in any cell line differentiation, the next cycle should not 
be delayed and no dose adjustment made. 
If the decrease in WBC or ANC or platelets is greater than 50% from that prior to treatment, with no 
improvement in cell line differentiation, the next cycle of azacitidine therapy should be delayed until the platelet 
count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. 
However, if recovery has not been achieved within 14 days, bone marrow cellularity should be determined. If 
the bone marrow cellularity is > 50%, no dose adjustments should be made. If bone marrow cellularity is 
≤ 50%, treatment should be delayed and the dose reduced according to the following table: 
 
Bone marrow cellularity 
% Dose in the next cycle if recovery is not achieved within 14 days 
 
Recovery* ≤ 21 days 
Recovery* > 21 days 
15-50 % 
100% 
50% 
< 15% 
100% 
33% 
*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count]) 
Following dose modifications, the cycle duration should return to 28 days. 
Dose adjustment due to non-hematologic toxicities:  
Renal abnormalities and electrolyte imbalance:  
- If unexplained reductions in serum bicarbonate levels to less than 20 mmol/L occur, the dose should be 
reduced by 50% on the next cycle. 
- 
If unexplained elevations in serum creatinine or blood urea nitrogen (BUN) to ≥ 2-fold above baseline 
values and above upper limit of normal (ULN) occur, the next cycle should be delayed until values return 
to normal or baseline and the dose should be reduced by 50% on the next treatment cycle. 
 
 






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Table (9.3) 1 - Biomarker sample collection plan 
Sample type 
Visit / time points 
Volume 
Marker 
Purpose 
Blood samples 
(PBMCs or 
fixed/lysed blood 
samples) 
LID1: S64315 predose 
CxD1: azacitidine predose 
CxD2: azacitidine predose, S64315 
predose, 1h and 24h ±2h EoI 
Any time in case of disease 
progression**** 
10 mL (EDTA K2 
tube) at each time 
point 
Bcl-2 family 
members protein 
expression 
To characterize PD 
markers and 
identify potential 
predictors of 
efficacy 
L1D1: predose 
C1D1: azacitidine predose 
C2D1: azacitidine predose 
C3D1: azacitidine predose 
In case of CR and every 3 months 
during study treatment period after 
CR for MRD only 
Any time in case of disease 
progression**** 
10 mL (EDTA K2 
tube) at each time 
point 
Genomic 
alterations of Bcl-2 
family members 
and cancer related 
genes 
To assess potential 
mechanisms of 
treatment resistance 
Detection and 
quantification of 
residual leukemic 
cells by gene 
expression and 
genomic 
alterations 
To assess MRD 
Blood samples 
LID1: S64315 predose 
C1D1: azacitidine predose 
C1D2: azacitidine predose, S64315 
predose, 4h, 6h, 24h and 72h after 
EoI 
C1D9: predose and 24h after EoI 
C1D16: predose 
Other cycles: CXD1 Aza predose; 
CXD16 predose 
According to local 
procedures (2 - 
4mL maximum) 
Absolute count of 
Total and B 
lymphocytes 
To assess potential 
surrogate response 
marker of 
biological activity 
as additional 
evidence of MCL-1 
response 
Bone Marrow 
Aspirate (BMA)* 
(BMMCs or 
fixed/lysed BMA 
samples) 
Baseline*** 
Any time in case of response (at 
least PR) 
In case of disease progression**** 
2-5 mL (EDTA K2 
tube) at each time 
point 
Bcl-2 family 
members protein 
expression 
Exploratory 
analysis for 
potential predictive 
markers of response 
Baseline*** 
C2D1: predose 
C3D1: predose 
In case of CR and every 3 months 
during study treatment period after 
CR for MRD only 
Any time in case of disease 
progression**** 
2-5 mL (EDTA K2 
tube) at each time 
point 
Genomic 
alterations of Bcl-2 
family members 
and cancer related 
genes 
To assess potential 
mechanisms of 
treatment resistance 
Detection and 
quantification of 
residual leukemic 
cells by gene 
expression and 
genomic 
alterations 
To assess MRD 
Archived BMB 
sample (and 
corresponding 
pathology report if 
needed)**  
(if available) 
Before screening 
FFPE tumour 
block or 15-20 
unstained slides 
Bcl-2 family 
members protein 
expression 
To assess potential 
Bcl-2 family 
members 
expression due to 
prior therapy 
BMB sample**  
(if available) 
Baseline*** 
Any time in case of response (at 
least PR) 
In case of disease progression**** 
FFPE tumour 
block or 15-20 
unstained slides 
 
Bcl-2 family 
members protein 
expression 
Exploratory 
analysis for 
potential predictive 
markers of response 
 
To assess potential 
mechanisms of 
treatment resistance 


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Sample type 
Visit / time points 
Volume 
Marker 
Purpose 
Saliva sample 
Baseline*** 
In case of CR 
Patient kit 
DNA/RNA 
sequencing 
Comparator to 
allow identification 
of somatic DNA 
variants in tumour 
Copies of karyotype 
reports (if available) 
Diagnosis and/or baseline*** 
In case of disease progression**** 
N/A 
Chromosomal 
abnormalities 
To assess potential 
modifications in 
karyotypes 
BMMCs: Bone Marrow-derived Mononuclear Cells; BMB: Bone Marrow Biopsy, PBMCs: Peripheral Blood-derived 
Mononuclear Cells; FFPE: Formalin-Fixed Paraffin-Embedded 
CR: complete response; PR: partial response 
*If enough material is available from the BMA performed for the evaluation of efficacy measurement (anti-leukemic activity) 
** If enough material is available from the BMB performed for the evaluation of efficacy measurement (anti-leukemic activity) 
***Before the first IMP administration 
**** N/A for LID period 
9.3.1. 
Mandatory assessments 
Tumour samples will be analysed at the molecular and cellular levels as well as to determine 
how baseline biomarker values/levels and changes from baseline may relate to exposure, 
clinical outcomes, and resistance. Potential predictive markers of efficacy will also be explored. 
In addition, MRD (Ivey, 2016) assessment will be explored for detection, as well as the 
quantification, of residual leukemic cells and their clonal evolution. 
Participation in the CL1-64315-004 study implies a systematic participation in the mandatory 
investigation. All patients will have to consent to this investigation by signing the main 
information and consent form for participation in the study. In addition, in case of consent 
withdrawal, related samples will be destroyed after mandatory assessment is completed. 
In this investigation, the analysis of an association between the biomarkers (BCL-2 family 
member genes, proteins and other genes of interest), the investigated disease (AML) and the 
treatment response will be assessed. For this purpose, samples from all patients will be collected 
in order to extract DNA, RNA and/or proteins and to analyse biomarkers (such as variations of 
DNA, proteins and RNA characteristics). Overall validated results of the biomarkers 
assessment may be transmitted to the patient upon his/her request at the end of the study. There 
will be no communication of individual results neither to the investigator nor to the patient 
unless these results are proven to impact the therapeutic strategy. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g. inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection analysis may be omitted at the discretion 
of the Sponsor. 
9.3.1.1. 
Sampling and storage 
Archived and newly obtained tumour samples but also blood samples will be collected before 
and during treatment with S64315 in combination with azacitidine upon disease progression to 
investigate the effect of the combination. 


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­ Archived and/or newly BMB: 
An archived tumour sample, Formalin-Fixed Paraffin-Embedded (FFPE) block, or unstained 
slides if it’s not possible to obtain FFPE block, is requested from all patients before screening, 
if available. The BMB main anatomo-pathological characteristics will be collected via the 
eCRF. If needed, corresponding copies of anonymized pathology reports should be sent to the 
Sponsor by fax or email to the following number / address: +33.1.55.72.50.04 / CL1-64315-
004@servier.com. An additional archived sample may be requested if the original sample 
provided is of insufficient quantity or quality to complete the planned analysis. All FFPE blocks 
and unstained slides will be stored and sent at approximately +4°C. 
­ Bone marrow aspiration (BMA) samples and blood samples: 
The BMA main anatomo-pathological characteristics will be collected via the eCRF. If needed, 
corresponding copies of anonymized pathology reports should be sent to the Sponsor by fax or 
email to the following number / address: +33.1.55.72.50.04 / CL1-64315-004@servier.com. 
BMMCs (bone marrow-derived mononuclear cells) or fixed/lysed cells and PBMCs (peripheral 
blood-derived mononuclear cells) or fixed/lysed cells collections from BMA and blood samples 
respectively are requested for all patients at various predose time points as described in 
Table (9.3) 1. PBMCs and BMMCs (or fixed/lysed cell) samples will be stored at 
approximately ≤ -70°C on site before shipment and sent on dry ice. 
­ Saliva: 
Patient’s saliva will be collected as defined in Table (9.3) 1. Patient’s saliva kit will be stored 
on site before shipment and sent at ambient temperature. 
­ Karyotype for AML patients: 
The main chromosomal abnormalities will be collected via the eCRF. If needed, copies of 
anonymized karyotype reports should be sent to the Sponsor by fax or email to the following 
number / address: +33.1.55.72.50.04 / CL1-64315-004@servier.com, if performed at the 
following time points: diagnosis, baseline (before the first infusion of S64315) and at disease 
progression. 
The samples will be stored during the study in a logistic platform/central laboratory. Then, the 
samples will be kept deep frozen (except for biopsy samples) in a central bio-repository 
specialized in storage of biological samples until further notification from the Sponsor and may 
be retained up to 25 years after study closure. 
9.3.1.2. 
Labelling and shipments 
All sample collection information must be entered as required on the appropriate sample 
collection eCRF page(s) and requisition form(s). Detailed instructions for the collection, 
handling, and shipment of tumour or other samples are outlined in the laboratory manual for 
the study. 
All tubes will be produced by the logistic CRO, and will be clearly labelled with the centre 
number, the patient number, date and hour of collection. Samples will be single coded with a 
number and thus will not carry any personal identifiers. 


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Samples will be sent to the logistic CRO to be stored until their analysis by different analytical 
laboratories depending on their aim: 
­ on dry ice for PBMCs and BMMCs (or fixed/lysed cells) from blood and BMA samples 
respectively 
­ at +4°C for archived and/or newly obtained tumour samples (BMB) 
­ at ambient temperature for patients’ saliva samples 
9.3.1.3. 
Biomarker assessments 
­ Archived and/or newly BMB 
Collection of the archived samples may allow monitoring of the changes potentially occurring 
in Bcl-2 family member’s expression, between the time of the collection of archived and newly 
obtained BMB. This could allow assessing potential Bcl-2 family member’s expression changes 
due to prior therapy. 
Newly BMB will be collected for exploratory analysis of potential predictive biomarkers of 
efficacy (response and non-response) which include but are not limited to expression of Bcl-2 
family proteins or other proteins related to cancer. 
Additional biomarkers or methods may be utilized if indicated by new findings from the 
literature as well as from I.R.I.S. internal data. 
­ BMA samples and blood samples 
BMMCs and PBMCs isolated from BMA and blood (or fixed/lysed cells) samples 
respectively will permit exploratory analysis of: 
 Predictive markers of efficacy (response and non-response) which may include, but are 
not limited to expression of Bcl-2 family proteins, genomic alterations of BCL-2 family 
member genes and other genes related to cancer using technologies such as next 
generation sequencing (NGS), 
 MRD and residual leukemic cells clonal evolution. 
Moreover, PBMCs isolated from blood samples will also be collected prior to and after dosing 
of S64315, on the time points indicated in Table (9.3) 1 to allow assessment of 
pharmacodynamics biomarkers.  
A dose-dependent decrease of B-cells counts following S64315 treatment has been observed in 
toxicological studies in rats. Moreover, based on literature, hypomethylating agents do not 
significantly reduce the B-cell population (N. Daver et al. Leukemia (2018)). Therefore, 
absolute count of total and B lymphocytes will be assessed locally as potential surrogate 
response markers for MCL1 inhibition.  
 
For patients who have disease progression after demonstrating clinical benefit, tumour samples 
may be collected and used to evaluate determinants of resistance and outcome as described 
above. Refractory tissue samples containing tumour (i.e. blood, BMA or BMB) will be 
compared to pre-treatment biopsy samples. 
Additional markers or methods may be utilized if indicated by new findings from the literature 
as well as from Sponsor’s internal data. 


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­ Saliva 
For gene alteration analysis, patient’s saliva will be used as a comparator to allow identification 
of somatic DNA variants in tumour. 
­ Karyotype 
The changes in karyotypes of AML patients related to S64315 treatment will be evaluated by 
comparing karyotypes at diagnosis or at baseline and at progression.  
The samples may be used after the end of the study for other genomic assessments in relation 
to the test drug or the disease (AML) not specified in the protocol in light of new scientific 
knowledge or technology but will not be used for the elaboration of a DNA bank. 
9.3.1.4. 
Transfer of analytical results 
Final analytical results will be transferred to Data Management according to section 12.2. 
9.3.2. 
Optional assessments 
During the trial, in addition to the biomarkers specified above, exploratory biomarker research 
may be conducted on any remaining BMA, tumour and/or blood samples. These studies would 
extend the search for the potential of other relevant biomarkers for S64315 in combination with 
azacitidine effects and/or safety. This may also include research to help develop ways to detect, 
monitor and/or treat cancer. These additional investigations would be dependent upon clinical 
outcome, reagent and sample availability. 
Participation in the CL1-64315-004 study does not imply a mandatory or systematic 
participation in these optional investigations. All voluntary patients will have to sign a specific 
informed consent form for optional retrospective genomic biomarker analyses. The consent 
given to these assessments can be withdrawn at any moment without compromising the 
participation in the overall clinical study investigations. In addition, in case of consent 
withdrawal, related samples will be destroyed before any optional assessment is completed. 
The samples will not be used for any investigations not specified in this protocol or for the 
elaboration of a DNA bank. 
If the patient agrees, the remaining biological samples from blood, bone marrow or tumour may 
be stored for up to 25 years and further analysed to address scientific questions related to the 
S64315 compound and/or cancer. This may also include research to help develop ways to 
detect, monitor or treat cancer. A decision to perform such exploratory biomarker research 
studies will be based on outcome data from this study or from new scientific findings related to 
the drug class or disease, as well as reagent and assay availability. 
9.3.2.1. 
Sampling and storage 
See section 9.3.1.1. 
9.3.2.2. 
Labelling and shipments 
See section 9.3.1.2. 
9.3.2.3. 
Transfer of analytical results 
See section 9.3.1.4. 


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9.4. Pharmacogenomics measurements 
In order to improve the knowledge of factors influencing S64315 pharmacokinetics in humans 
and in accordance with the guideline ‘Guideline on the use of pharmacogenetic methodologies 
in 
the 
pharmacokinetic 
evaluation 
of 
medicinal 
products’ 
(Guideline 
EMA-
EMA/CHMP/37646, 2009), an analysis of genetic variations among patients is recommended. 
This investigation focuses on genes encoding proteins involved in absorption, distribution, 
metabolism and excretion (ADME) will be requested if a high inter-individual variability would 
be observed in pharmacokinetics data not explain by other factors (as gender, age, body weight, 
etc.). Therefore, depending on the results obtained during the study, sample analysis may be 
omitted at I.R.I.S. discretion. 
Participation in the CL1-64315-004 study does not imply a mandatory or systematic 
participation in the optional investigation. All voluntary patients will have to sign a specific 
informed consent form for optional genomic biomarkers (ADME genotyping) analysis. The 
consent given to this assessment can be withdrawn at any moment without compromising the 
participation in the overall clinical study investigations. In addition, in case of consent 
withdrawal, related samples will be destroyed before any optional assessment is completed. 
The samples will not be used for any investigations not specified in this protocol or for the 
elaboration of a DNA bank. 
Overall results of the pharmacogenomics ADME biomarkers assessment may be transmitted to 
the patient upon his/her request at the end of the study. There will be no communication of 
individual results neither to the investigator nor to the patient. 
9.4.1. 
Sampling and storage 
One blood sample (2 mL) per patient will be collected into an EDTA K3 tube according to the 
study centre’s practice at C1D1 azacitidine predose. The accurate sample collection date and 
time must be recorded on the requisition forms and entered on the sample collection eCRF page. 
The blood sample will be immediately stored on site before shipment and sent on dry ice. 
9.4.2. 
Labelling and shipments 
Each sample tubes will be clearly labelled with a double identification (aliquot number, 
Sponsor’s name, country code, centre number, protocol number and patient number) and will 
be shipped with a requisition form. Samples will be single coded with a number and thus will 
not carry any personal identifiers. 
The whole blood samples will be stored on site before shipment at approximately ≤ 70°C and 
sent on dry ice to the appropriate logistic CRO that will store the samples at approximately 
≤-70°C at reception, until shipment to the laboratory for DNA extraction and analysis. The 
extracted remaining DNA samples will then be shipped and kept deep frozen in a central bio-
repository specialized in storage of biological samples or not until further notification from the 
Sponsor and may be retained up to 25 years after study closure. 
The samples may be used after the end of the study for ADME genomic assessments in relation 
to the IMPs not specified in the protocol in light of new scientific knowledge or technology. 
After a maximum period of 25 years after the end of the study or on the simple demand of the 
patient to the investigator, all DNA extracts stored at a central bio-repository will be destroyed. 


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9.4.3. 
Transfer of analytical results 
If the analysis is required during the study, final analytical results will be transferred to Data 
Management; otherwise no data will be transferred. 
10. STATISTICS 
This part will describe the planned analysis for the Arm A and the sub-arms A1 and A2. 
Arm B will be introduced through an amendment and the associated statistical part will be 
defined later. 
10.1. Overall consideration 
The purpose of this study is to determine the safety profile, the maximum tolerated dose (MTD), 
the dose-limiting toxicity (DLT(s)), the RP2D and to investigate the clinical activity of the 
combination of S64315 with azacitidine in patients with AML. 
The dose escalation phase I part will be followed by an expansion phase II part into two sub-
arms: A1 and A2. A DSMB will assess the overall data of the study and provide 
recommendations on the conduct of the study (see section 8.11). The statistical analyses 
corresponding to the dose allocation processes will be carried out using R software with the 
rjags R package (Rjags R) by the Center of Excellence Methodology and Valorisation of Data 
of I.R.I.S. 
10.2. Dose escalation phase I part 
10.2.1. Dose escalation phase I part considerations 
An adaptive Bayesian Logistic Regression Model (BLRM) with overdose control (EWOC) will 
be used to guide the dose escalation phase I part and estimate the MTD(s) based on occurrence 
of DLT until C1D28 (Neuenschwander, 2008; Babb, 1998). 
The BLRM is a well-established method to estimate the MTD in patients with cancer. The 
adaptive BLRM will be guided by the escalation with overdose control principle to control the 
risk of DLT in future patients on study. The dose recommended by the model at any stage of 
the trial is based on the entire history of all available DLT information from previous cohorts 
as opposed to only the number of DLTs observed in the last group of patients. Moreover, 
historical data/co-data can also be used to enrich the prior of the BLRM. Operational 
characteristics of the design are presented in Appendix 8. 
This study is currently planned to administer S64315 once a week during a 28-day cycle in 
combination with azacitidine, with a lead-in dose period of 2 weeks for S64315. 
Based on the emerging clinical safety and PK data, other dosing schedules may also be assessed 
in this study. If the decision is made to switch to a different dosing schedule a new model and 
its operating characteristics will be communicated via a new document similar to Appendix 8 
along with the documentation provided as formal notification of the change in dosing schedule 
(e.g. minutes of the corresponding dose escalation meeting, etc.), or it will be explicitly 
indicated in such documentation with suitable rationale that the new regimen has no changes to 
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The MTD/RP2D will be based on: 
­ The MTD estimated by the BLRM model stated above and 
­ An overall clinical assessment of all available safety, tolerability, PK, PD and preliminary 
activity data 
10.2.2. Statistical model 
This part contains a quick presentation of the model; more details about the model and 
assumptions are presented in Appendix 8, as well as the operational characteristics of the chosen 
models. 
A 5-parameter adaptive Bayesian logistic regression model guided by the escalation with 
overdose control principle (EWOC) will be fitted on DLT during LID period and during Cycle 
1 data to make dose recommendations and estimate the MTD/ RP2D for the combination of 
S64315 (agent 1) and azacitidine (agent 2, fixed dose). 
The model has three components: 
­ S64315 single agent toxicity, represented by parameters α1 and β1 
­ azacitidine single agent toxicity, represented by parameters α2 and β2 
­ the interaction between S64315 and azacitidine, represented by parameter η12 
The two single agent dose-DLT relationships are modelled as in a single agent study: 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙൫𝜋𝜋1(𝑑𝑑1)൯=  𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼1) +  𝛽𝛽1 𝑙𝑙𝑙𝑙𝑙𝑙(𝑑𝑑1/𝑑𝑑1 ∗), 𝛼𝛼1 > 0, 𝛽𝛽1 > 0 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙൫𝜋𝜋2(𝑑𝑑2)൯=  𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼2) +  𝛽𝛽2 𝑙𝑙𝑙𝑙𝑙𝑙(𝑑𝑑2/𝑑𝑑2 ∗), 𝛼𝛼2 > 0, 𝛽𝛽2 > 0 
where π1(d1) is the probability of DLT if S64315 is given as a single agent at a total weekly 
dose of d1 and π2(d2) is the probability of DLT if azacitidine is given as a single agent at a total 
daily dose of d2. 
The parameter α1 (respectively α2) is then the single-agent odds of a DLT at the reference dose 
for S64315 (respectively azacitidine), and β1 (respectively β2) is the increase in the log-odds 
of a DLT by a unit increase in log-dose for S64315 (respectively azacitidine). As there is only 
one tested dose of azacitidine and this tested dose is chosen as the reference dose, log(d2/d2*) = 
0 and β2 will not be estimated. Then, the model is simplified from a 5-parameter model to a 4-
parameter model. 
The dose-DLT relationship of the combination of S64315 and azacitidine is modelled as: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂(𝜋𝜋12(𝑑𝑑1, 𝑑𝑑2))) =
𝜋𝜋12(𝑑𝑑1, 𝑑𝑑2)
1 − 𝜋𝜋12(𝑑𝑑1, 𝑑𝑑2)
=   𝑒𝑒𝑒𝑒𝑒𝑒(𝜂𝜂12 𝑑𝑑1
𝑑𝑑1 ∗
𝑑𝑑2
𝑑𝑑2 ∗) ൬𝜋𝜋1(𝑑𝑑1) +  𝜋𝜋2(𝑑𝑑2) − 𝜋𝜋1(𝑑𝑑1)𝜋𝜋2(𝑑𝑑2)
(1 − 𝜋𝜋1(𝑑𝑑1))(1 − 𝜋𝜋2(𝑑𝑑2))
൰ 
This study is currently planned to administer S64315 once weekly with a 28-day cycle preceded 
by a LID period of 2-weeks, with one infusion of 25 mg on D-13 and one infusion of 50 mg on 
D-6. Azacitidine will be administered at 75 mg/m² via SC injection, daily for 7 days, from D1 
to D7 followed by a rest period of 21 days (28-day cycle). However, based on the emerging 
clinical safety and PK data, other dosing schedules may also be assessed in this study. 


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If the decision is made to switch to a different dosing schedule before determination of the MTD 
in the planned schedule, then the initial total weekly S64315 dose will be a dose that has 
previously been tested and that is considered safe according to the EWOC criterion. Unless 
otherwise justified, it will be assumed that different schedules can have different effects on 
patient safety and dose allocation based on the new schedule will then be guided by a new 
model. 
The new model and its operating characteristics would be communicated via a new document 
similar to Appendix 8 along with the documentation provided as formal notification of the 
change in dosing schedule (e.g. minutes of the corresponding dose escalation meeting, etc.), or 
it would be explicitly indicated in such documentation with suitable rationale that the new 
regimen has no change to the initial model. 
The MTD is the highest dose of the combination treatment that is unlikely (< 25% posterior 
probability) to cause DLT in more than 33% of the treated patients during the LID period and 
the first cycle of S64315 treatment in combination with azacitidine. 
10.2.3. Provisional dose levels 
This study currently plans and expects to complete dose escalation of S64315 in combination 
with azacitidine with the provisional dose levels described in Table (10.2.3) 1. 
Table (10.2.3) 1 - Provisional dose levels 
Dose level 
-1 
1* 
2 
3 
4 
Weekly dose of S64315 (mg) 
25 
50* 
100 
200 
250 
*Starting 
dose 
level 
according 
to 
the 
power 
prior 
obtained 
by 
integrating 
all 
data 
from 
weekly  
S64315 in the single agent CL1-64315-004 study validated at the last EoC meeting 
Intermediate dose levels could be added during the course of the study. 
Azacitidine will be administered at a fixed dose of 75 mg/m² via SC injection, daily for 7 days, 
from D1 to D7 followed by a rest period of 21 days (28-day cycle). 
S64315 full starting dose will be 50 mg. This dose is considered safe (i.e. fulfilling the EWOC 
criterion) according to the power prior obtained by integrating all data from the weekly schedule 
of S64315 as a single agent in CL1-64315-001 study validated in an EoC meeting (see 
Appendix 8 for details on power prior calculation and power prior obtained from single agent 
study data as of 26 November 2019). 
10.2.4. Prior specifications 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which includes the single-agent parameters for S64315 (α1, β1), for azacitidine (α2, β2), and 
the interaction parameter (η12). A weakly informative prior will be used for S64315 prior and 
data from study CL1-64315-001 will be used to enrich this same weakly informative prior. 
Details on the derivation of the weakly informative prior that will be used are provided in 
Appendix 8. A weakly informative prior will be used for azacitidine. 


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10.2.5. Integration of data from CL1-64315-001 study as co-data 
Available clinical data from CL1-64315-001 study will be used to enrich the weakly 
informative prior used in our combination, in a down weighted fashion. The power prior 
obtained after integration of the previous study data will be used as prior information for 
S64315: it will be derived at the time of evaluation of each once a week cohort in combination 
with azacitidine, based on all data from the weekly monotherapy schedule (study CL1-64315-
001) validated in an EoC meeting at that time. 
The given data will be incorporated through down-weighting using the following weight ‘w’ 
(Chen, 2006; Neuenschwander, 2010): 
𝑤𝑤= 
1
1 + 2𝑛𝑛𝜏𝜏2/𝜎𝜎2 
where n is the sample size of external data, σ is the ‘outcome standard deviation’ for one 
observation and τ is the between-trial standard deviation. While σ is the standard deviation of 
all external data which include several dose levels, 𝜎𝜎2 can be approximated by variance of 
log(α). For this dose escalation, σ was then chosen as 2 and τ was set as 0.25 to correspond to 
moderate between-trial variability. 
See Appendix 8 for details on power prior calculation and the power prior obtained study 
CL1-64315-001 data as of 26 November 2019. 
10.2.6. Dose proposed by the model 
The dose allocation will start at the dose combination of 50 mg and 75 mg/m2 respectively for 
S64315 and azacitidine.  
A maximum of 6 DLT-evaluable patients may be initially enrolled at a dose level, and a 
minimum of 3 DLT-evaluable patients must be treated at a given dose level before a new higher 
dose level may be evaluated. 
All available data on DLTs, assessed starting from the LID period to C1D28 will be used for 
updating the model. Before making a dose allocation decision, all patients from a cohort must: 
­ have been treated with LID1 and LID2, 3 out of 4 S64315 infusions and 5 out of 7 azacitidine 
injections or 
­ have had a DLT within the LID period or the first cycle 
If a patient is not eligible for inclusion in the Dose-Limiting Toxicity Evaluable Set (DLTES), 
she/he must be replaced. 
If a DLT occurred at LID1, the DLT will be considered as relative to 25 mg of S64315 in 
monotherapy. If a DLT occurred at LID2, the DLT will be considered as relative to 50 mg of 
S64315 in monotherapy. In that case, the patient will be replaced to ensure the minimal number 
of patients needed in the cohort at the full tested dose. Those DLTs will be considered for dose 
recommendation during the EoC meeting. 


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At any time during the study, if DLTs occur in the first 2 evaluable patients of a cohort (whether 
it happened during the LID period or cycle 1), the BLRM could be updated in order to re-
evaluate the current dose level before enrolment of any additional patients in the cohort. Once 
each cohort of patients is completed, the dose recommendation by the model will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories: 
­ [0,16%) under-dosing 
­ [16%,33%) targeted toxicity 
­ [33%,100%] excessive toxicity 
Following the principle of EWOC, after each cohort of patients, the dose combinations fulfilling 
the EWOC criterion (i.e. it is unlikely (<25% posterior probability) that the DLT rate at the 
dose falls in the excessive toxicity interval) will be identified by the model. A dose not fulfilling 
the EWOC criterion cannot be recommended. 
In addition, admissible dose increments for the next cohort will not exceed 100% of the previous 
dose of S64315. 
The set of allowed doses for the next cohort is thus defined as the intersection between the dose 
levels admissible according to this protocol (escalation rule defined above) and the dose levels 
allowed by the model (EWOC criterion fulfilled). The dose recommendation made by the 
adaptive BLRM should then be regarded as guidance and information to be integrated with a 
clinical assessment of the toxicity and activity profiles observed, so that a dose is selected for 
the next cohort among the allowed doses. 
 
More than 6 DLT-evaluable patients may be treated in a cohort at dose levels considered safe 
according to the BLRM with overdose control in order to better characterize the safety, 
tolerability, PK, PD, or preliminary clinical activity of S64315 in combination with azacitidine. 
10.2.7. Dose allocation process 
Once evaluation of a given dose level has been completed, and before testing a new dose level, 
an EoC meeting between the Sponsor (Therapeutic Area Oncology and Immuno Oncology, 
Medical Safety Leader, Methodology Department and Clinical Pharmacokinetics Department) 
and the investigators will take place to decide jointly the next dose level to be tested according 
to: 
­ the admissible doses allowed by the BLRM (based on single agent study CL1-64315-001 
data through the power prior) 
­ all safety data 
­ PK data 
­ PD data 
­ activity data 
The dose allocation process is described in Figure (10.2.7) 1. 
 


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Figure (10.2.7) 1 - Dose-allocation process 
 
 
10.2.8. Final recommendation and stopping rules 
Dose escalation will continue until identification of the MTD or suitable lower dose levels for 
the expansion phase II (RP2D). This will occur when the following conditions are met: 
1. at least 6 patients have been treated at this dose and are evaluable for the DLT 
2. one of the following conditions is fulfilled: 
a. 
the posterior probability of targeted toxicity at this dose exceeds 50% and is the highest 
among potential doses or 
b. a minimum of 18 patients have already been treated and evaluable for the DLT on the 
dose escalation of Arm A 
3. it is the dose recommended for patients, either per the model or by review of all patient 
clinical data during an EoC meeting 
New cohort of patients 
Observed DLTs 
throughout the study 
 
Re-evaluation of the 
Dose-DLT relationship 
with BLRM 
Admissible dose 
combination defined by 
the BLRM with EWOC 
Validation of the dose level 
combination allocation during 
EoC meeting 
Additional data (safety, 
PK, PD, activity, etc.) 
DSMB 
recommendation 
Observed DLTs throughout the  
CL1-64315-001 dose-escalation 
e.g. 0/3, 0/3, 1/3… 
Power prior 
 


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Of note, the dose escalation phase I part could be stopped earlier by a joint decision from the 
sponsor and the investigators during a dose escalation meeting, by taking into account the model 
estimations and a global assessment of the safety, PK, PD and preliminary activity data. Note 
that it is possible that the MTD may not be reached in some situations and a suitable dose level 
may be defined as a recommended dose for the phase II dose expansion part after evaluation of 
all data collected during the phase I dose escalation part. 
10.3. Expansion phase II part 
10.3.1. Expansion design 
The expansion phase II part will be performed at the MTD or suitable lower dose levels (RP2D) 
in order to gain more information about the overall safety and tolerability of S64315 in 
combination with azacitidine in Arm A, to provide additional PK and PD data and to provide 
preliminary activity data. 
Therefore, an expansion phase II part will be performed at the final recommended dose (RP2D) 
and schedule of administration in order to better evaluate anti-tumour activity and cumulative 
toxicity if any of S64315 in combination with azacitidine in sub-arms A1/A2. New patients will 
be enrolled in a two-stage expansion phase II part with a Bayesian interim analysis for futility 
at the end of stage 1 in each arm. 
During stage 1, in each arm, patients will be enrolled and treated at the corresponding RP2D. 
The interim analysis for futility will occur when the patients included in stage 1 have completed 
at least 4 cycles or early discontinued. Of note, the recruitment could be stopped before the 
interim analysis if the minimal number of responders is impossible to be met. 
Then, a Bayesian analysis will be performed on the rate of CR. Decision rules will be based on 
clinical threshold defined on the posterior distribution of the rate of CR (see section 8.5 for 
details on the determination of sample size). 
According to results of futility interim analysis performed at the end of stage 1, the expansion 
phase II part could be: 
­ Stopped, if results on the rate of CR are considered futile 
­ Continued if results on the rate of CR are considered not futile. In that case, additional 
patients will be enrolled in stage 2 
10.3.2. Criteria to re-evaluate the RP2D during the expansion phase 
Subjects in the dose expansion phase will be followed for DLT (as defined in section 4.1.3.5). 
After at least 4 subjects have been treated during dose expansion at the RP2D, if the observed 
rate of DLT through the end of Cycle 1 exceeds 33% across (including the patients treated at 
this dose during dose escalation), the BLRM will be updated to determine whether the RP2D 
still satisfies the EWOC principle. If the RP2D is estimated to have a ≥25% posterior probability 
of generating excessive toxicity (DLT rate between 33% and 100%) during the first cyle of 
treatment, then enrollment to the study will be paused. A risk assessment will be conducted by 
the DSMB, the investigators and sponsor, and consideration will be given to reducing the 
RP2D.  


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In addition, monitoring will continue for DLTs that may occur after the first cycle of treatment. 
After at least 4 subjects have had the opportunity to receive a second cycle of treatment, if the 
posterior probability (based on a beta-binomial distribution, using a Jeffrey prior) is greater than 
25% that the true rate of DLT occurring after Cycle 1 is >33%, enrollment to the study will be 
paused. Subjects should have received at least three doses of S64315 from Cycle 2 to be 
evaluable, unless dosing was limited by the occurrence of a DLT. Evaluable patients treated at 
this dose during dose escalation will also be included in this assessment. The study will also be 
paused if the cumulative rate of Grade ≥3 treatment-related cardiac adverse events at the RP2D 
exceeds 20%.  
In either case, the safety of the RP2D will be re-evaluated by the DSMB, the investigators and 
sponsor, and consideration will be given to reducing the RP2D.   
If the assessment of all available data warrants a change in the RP2D, 23 subjects will be treated 
at the new RP2D in each arm involved. These subjects will be monitored as reported above.  
10.4. Statistical analysis 
A Statistical Analysis Plan will be written after finalising the protocol and definitively 
completed before the first database lock. These specifications will detail the implementation of 
all the planned statistical analyses in accordance with the principal features stated in the 
protocol. 
The statistical analysis will be mainly descriptive. It will be carried out using SAS software 
by I.R.I.S. Pole of Expertise Methodology & Data Valorisation and/or designated CRO. 
The study data will be analysed and reported in the CSR once the study is terminated (at the 
end-of-study, defined as the date of the last follow-up of the last patient). However, some 
intermediate analyses might be performed during the conduct of the study. 
10.4.1. Evaluation criteria 
10.4.1.1. Safety criteria 
10.4.1.1.1. Dose escalation phase I part 
­ Incidence of DLT during the LID period and Cycle 1 
­ Incidence and severity of AEs and SAEs 
­ Change or addition of a new concomitant treatment 
­ Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood 
coagulation, urinary analysis, hepatitis markers, TLS monitoring, cardiac markers 
­ Complete physical examination, ECOG PS 
­ Vital signs 
­ ECG and cardiac function parameters 
­ LVEF 
­ Pregnancy test for WOCBP 
­ Dose interruptions, reductions and dose intensity 
10.4.1.1.2. Expansion phase II part 
Evaluation criteria for expansion phase II part for sub-arms A1 and A2 will be further defined 
according to the dose escalation phase I results of Arm A. 


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­ Incidence and severity of AEs and SAEs 
­ Change or addition of a new concomitant treatment 
­ Laboratory tests: haematology with differential, blood biochemistry, thyroid function, blood 
coagulation, urinary analysis, hepatitis markers, TLS monitoring, cardiac markers 
­ Complete physical examination, ECOG PS 
­ Vital signs 
­ ECG and cardiac function parameters 
­ LVEF 
­ Pregnancy test for WOCBP 
­ Dose interruptions, reductions and dose intensity 
10.4.1.2. Activity criteria 
The efficacy endpoints are defined according to guidelines (Guideline EMA, 2012) and 
(ICH E9, 1998). 
10.4.1.2.1. Dose escalation phase I part 
During the dose escalation phase I part, efficacy is only assessed as a secondary objective. 
The following endpoints are assessed according to the previous part of the protocol. 
­ Best Overall Response (BOR) observed during the treatment period, as defined by standard 
disease-specific criteria 
­ Objective Response Rate (ORR) will be defined as the proportion of patients who achieve a 
complete remission (CR), complete remission with incomplete hematologic recovery (CRi) 
and morphologic leukemia-free state (MLFS) according to ‘Diagnosis and management of 
AML in adults: 2017 ELN recommendations from an international expert panel’ (Döhner, 
2017) 
­ Complete Remission (CR) rate will be defined as the proportion of subjects who achieve 
complete remission (Döhner, 2017) 
­ Duration of response (DOR) will be calculated from the date of first response to the date of 
progression or the date of death (whatever the reason of death), whichever occurs first 
­ Progression-Free Survival (PFS) will be calculated from the date of first IMP administration 
to the date of progression or the date of death (whatever the reason of death), whichever 
occurs first 
­ Overall Survival (OS) will be calculated from the date of first IMP administration to the date 
of death (whatever the reason of death) 
­ Disease-Free Survival (DFS) will be defined on responders by the time from primary 
response to relapse 
10.4.1.2.2. Expansion phase II part 
The following endpoints are assessed according (Guideline EMA, 2012) and (ICH E9, 1998). 
­ Primary endpoint: 
 Complete Remission rate will be defined as the proportion of subjects who achieve 
complete remission  
­ Secondary endpoints: 
 Objective Response Rate (ORR) will be defined as the proportion of patients who achieve 
a complete remission (CR), complete remission with incomplete hematologic recovery 
(CRi) or morphologic leukemia free-state (MLFS) 


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 Best Overall Response (BOR) observed during the treatment period, as defined by 
standard disease-specific criteria 
 Duration of response (DOR) will be calculated from the date of first response to the date 
of progression or the date of death (whatever the reason of death), whichever occurs first 
 Overall survival (OS) will be calculated from the date of first IMP administration to the 
date of death (whatever the reason of death) 
 Progression Free Survival (PFS) will be calculated from the date of first IMP 
administration to the date of progression or the date of death (whatever the reason of 
death), whichever occurs first 
 Disease-Free Survival (DFS) will be defined on responders by the time from primary 
response to relapse 
10.4.2. Statistical elements 
The following descriptive statistics will be provided depending on the nature of variables: 
­ Quantitative variable: number of observed values, mean and standard deviation, minimum 
and maximum and if necessary, median, first and third quartiles 
­ Qualitative or ordinal variable: number and percentage by class 
10.4.3. Analysis sets 
The following analysis sets are defined according to (ICH E9, 1998) guidelines. 
10.4.3.1. Dose escalation phase I part 
­ Included Set 1 (IS1) corresponds to all included patients during the dose escalation phase I 
part 
­ Safety Set 1 (SS1) corresponds to patients who received at least one dose of IMP during dose 
escalation phase I part. It will be used for all safety and efficacy analyses 
­ Dose-Limiting Toxicity Evaluable Set (DLTES) corresponds to patients from the SS 1 who 
are evaluable for DLT according to the criteria defined in section 4.1.3.6 
10.4.3.2. Expansion phase II part 
­ Included Set 2 (IS2) corresponds to all included patients during the expansion phase II part 
­ Safety set 2 (SS2) corresponds to patients who received at least one dose of IMP during the 
expansion phase II part 
­ Per protocol set (PPS) corresponds to patients of SS2 that do not have any significant 
protocol deviations that may impact the primary endpoint (CR rate). The list of deviations 
will be reviewed for the determination of their significance prior to the database lock 
10.4.4. Statistical methodology 
All the following analyses will be performed separately. When they are done on expansion 
phase II part, analyses will be done on each sub-arm A1 and A2 separately. 
10.4.4.1.  Study outcome 
The study outcome analyses will be carried out on the IS sets, IS1 and IS2, by dose level and 
overall. 
Patients characteristics including demography, disease characteristics at diagnosis and 
assessment criteria baseline values will be described. 


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Number of cycles, dose intensity, dose interruptions, patient status, withdrawal reason, protocol 
deviations and concomitant treatments will be described. 
10.4.4.2. Safety 
The safety analyses will be performed on the SS sets, SS1 and SS2, by dose level and overall. 
DLT until the end of Cycle 1 
Number and percentage of patients in the DLTES with DLT occurrence from the LID period to 
the end of the first cycle will be tabulated by dose level and overall. 
DLT after the end of Cycle 1  
Number and percentage of patients evaluable for DLTs, with occurrence of DLT after the end 
the first cycle will be tabulated by dose combination and overall. 
Emergent adverse event 
NCI CTCAE v5.0 will be used to classify all adverse events. 
Number of Emergent adverse event (EAE), number and percentage of patients reporting at least 
one EAE will be summarised by System Organ Class and Preferred Term, overall and by dose 
level. The same analysis will be performed for serious EAEs and SAEs. 
Some analyses will be performed by worst on-treatment grade, severity, relationship to the IMP, 
outcome and action taken. 
Clinical laboratory evaluation 
Laboratory parameters will be graded according to NCI CTCAE v5.0. For laboratory tests 
where grades are not defined by NCI CTCAE v5.0, results will be classified according to the 
laboratory reference ranges. 
The following summaries will be generated separately for each haematology and biochemistry 
tests: 
­ for laboratory tests where grades are defined by NCI CTCAE v5.0, shift tables comparing 
the worst on-treatment grade to the grade at baseline 
­ for laboratory tests where grades are not defined by NCI CTCAE v5.0, shift tables comparing 
the classification according to the laboratory normal ranges to baseline 
Urinalysis abnormalities will be described using shift tables comparing the worst on-treatment 
value (Positive, Trace, Negative) to the value at baseline. 
Physical examination including vital signs, body weight and ECOG PS 
These criteria will be described using baseline value, worst on-treatment value and change from 
baseline to worst on-treatment value. 
ECG parameters and LVEF 
Quantitative parameters (QT interval corrected and LVEF) and qualitative parameters (ECG 
abnormalities) will be described. 
10.4.4.3. Activity 
One of the objectives of the study is to assess preliminary anti-tumour activity of S64315 in 
combination with azacitidine. 


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10.4.4.3.1. Dose escalation phase I part 
CR rate, BOR and ORR will be analysed on the SS1 by dose level, overall and per population 
(relapsed/refractory and 1st line) depending of the number of patients. They will be evaluated 
according to the investigator assessments of response during the treatment period. They will be 
described using proportion and the corresponding exact binomial 95% confidence interval will 
be provided. 
The survival function of the time-dependent parameters will be estimated via Kaplan-Meier 
curve. In addition, 95% confidence interval for median duration will be computed depending 
of the number of observations 
10.4.4.3.2. Expansion phase II part 
The primary endpoint Complete Remission rate will be analysed on the SS2 and on the PPS 
depending of the number of patients per treatment status. 
Patients without post-baseline assessment will be considered as non-responders. 
The Complete Remission rate will be described using proportion along with the corresponding 
exact binomial 95% confidence interval. Bayesian statistics based on the posterior distribution 
will also be provided. 
The secondary endpoints, ORR, BOR, DOR, OS, PFS and DFS will be analysed on the SS2 
and on the PPS, overall and per treatment status (R/R and 1st line) depending of the number of 
patients per treatment status. 
BOR will be described using proportion along with the corresponding exact binomial 95% 
confidence interval. 
The distribution of the survival endpoints (OS, DOR, DFS and PFS) will be estimated with the 
Kaplan-Meier product-limit method. Summary statistics (median, 95% confidence interval) and 
Kaplan-Meier curves will be presented.  
All endpoints will be evaluated according to the investigator assessments of response during 
the period of interest. 
10.4.4.4. Biomarkers 
The relationship between the expression level of Bcl-2 family members, genomic alterations of 
Bcl-2 family member genes and other cancer-related genes in blasts (from blood and bone 
marrow samples) as well as target-engagement biomarker and the antineoplastic activity of 
S64315 in combination with azacitidine could be studied using descriptive statistics if relevant, 
and quantitative systems pharmacology analyses. The relationship between the biomarkers just 
mentioned and S64315 toxicity could also be studied using descriptive statistics. 
10.5. Determination of sample size 
No formal statistical power calculations to determine sample size were performed for this study. 
Overall, a maximum of 180 patients will be enrolled in the dose escalation phase I part of Arm 
A (up to 30 patients) followed by sub-arms A1and A2 (50 per sub-arms, up to 150 patients 
overall). 
10.5.1. Dose escalation phase I part 
During the dose escalation phase I part, the cohort size will be between 3 and 6 evaluable 
patients. At least 6 patients will be treated at the MTD/RP2D level, as described in section 10.2. 


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According to the simulations performed, at least 18 patients should be considered evaluable in 
the dose escalation phase I part to have reasonable operating characteristics for the 
determination of the MTD. However, in some situations, the MTD/ RP2D could be declared 
with fewer patients. 
10.5.2. Expansion phase II part 
In the expansion phase II part, up to 50 patients will be enrolled in each sub-arm (A1 and A2) 
at the RP2D. In each of these arms, there will be two stages: 
­ 23 patients are planned to be included in stage 1 based on the following Bayesian rules for 
futility: the posterior probability of CR rate <20% must be lower than 60% (i.e. >4 (so at 
least 5) responders /23 patients) to consider there is enough evidence of S64315 in 
combination with azacitidine activity to enrol a new cohort in stage 2 
­ In case of no futility at the end of stage 1, 27 additional patients are planned to be included 
in stage 2. This number of patients ensures detecting enough evidence of S64315 in 
combination with azacitidine activity based on a posterior probability of CR rate >20% 
greater than 70%. Moreover, this number of patients has been identified to ensure a minimal 
precision of 23% around the CR rate 
10.6. Pharmacokinetic analyses and PK/PD analysis 
10.6.1. Pharmacokinetic interpretation 
The dataset needed for the final analysis will be prepared by extraction from the clinical 
Business Intelligence Department using SAS® program and following the clinical PK project 
manager specifications. The non-compartmental pharmacokinetic analysis (NCA) will be 
performed by the Clinical Pharmacokinetics and Pharmacometrics Department using 
PhoenixWinNonlin® version 6.4 or later or Excel 2010 on the individual plasma concentration-
time data of S64315 and azacitidine after the IV administration of S64315 and SC 
administration of azacitidine. 
For S64315 and azacitidine preliminary NCA analysis, the theoretical administration and 
sampling times will be used. 
The exact administration and sampling times will be used for the final NCA analysis for S64315 
and azacitidine. 
Descriptive statistics, tables and figures will be generated using SAS 9.2® and Excel® 2010. 
The NCA will be performed according to operating manual (OPM) of clinical Pharmacokinetics 
and Pharmacometrics Department. 
Any suspicious concentration will be investigated and kept in the PK analysis if possible. All 
excluded concentrations will be justified in the report. 
For each patient, the following parameters will be calculated on the individual plasma 
concentration-time profiles of azacitidine: Cmax, tmax, AUClast, AUCτ, AUC, tlast, Clast, t1/2,z, 
CL and Vd. 
For each patient, the following parameters will be calculated on the individual plasma 
concentration-time profiles of S64315: Cinf, tinf, AUClast, AUCτ, AUC, tlast, Clast,, t1/2,z, CL and 
Vd. 
Descriptive statistics (n, mean, SD, min, median, max, coefficient of variation) will be 
calculated for these PK parameters as well as on concentrations-time profiles using SAS and 
Excel®. 


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S64315 plasma concentrations from the present study that could be pooled with data from 
previous studies will be analysed by population approach, described in a separate Data Analysis 
Plan, in order to assess S64315 PK and to investigate potential sources of variability through a 
covariate analysis. 
10.6.2. PK/PD interpretation when applicable 
Any potential PK/PD relationships with activity, efficacy and safety will be investigated 
through an exploratory analysis, and if relevant, a PK/PD Data Analysis Plan will be set up. 
Description of analyses will be done in a separate PK/PD protocol. 
PK/PD relationship will be assessed for clinical and biological efficacy endpoints including: 
­ Clinical response according to (Cheson, 2003) 
­ Biological response: bonne marrow blast decrease 
­ Blood markers: WBC, neutrophils, platelets 
­ Any other clinically relevant endpoint 
PK/PD relationship will be assessed for clinical and biological safety endpoints including: 
­ Cardiac events following narrow and broad definitions as in section 8.2.5 
­ Plasma troponin I and troponin T 
­ Left ventricular ejection fraction 
­ Neutrophil count 
­ Hepatic safety parameters (i.e. AST, ALT) 
­ Any other clinically relevant endpoint 
Assessment of the PK/PD relationship for listed safety endpoints will be updated after each new 
cohort completion, when assessment of PK/PD relationship for efficacy will be performed at 
the end of dose escalation. 
PK and relevant biomarker data may also be analysed in a Quantitative Systems Pharmacology 
analysis, which will be described in a separate protocol. 
11. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IRB/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 is accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with 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 the monitoring guide. 


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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. 
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 eCRF (i.e. access to an analogic phone line or his/her computer) 
­ check that the eCRF has been filled out correctly 
­ directly access source documents for comparison of data therein with the data in the eCRF 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements 
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 patients 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 


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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 patients. 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 
patients 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 patients. 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 patients. 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, etc.) 
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 of 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 patients and, if 
the computer system used allows, the record of the changes made during the study. 


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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 patients 
­ 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 
12.4. Supervisory committees 
The 
DSMB 
will 
be 
composed 
of 
3 
members 
expert 
in 
haematology, 
gastroenterology/hepatology and cardiology. One of these experts will be the chairperson of 
this committee and his/her role is to coordinate, lead the DSMB meetings and deliver the 
minutes of the meetings to the Sponsor.  
According to the protocol design, the DSMB will meet after the last patient of each cohort has 
completed Cycle 1 during the dose escalation phase I part and then every 3 months, according 
to the recruitment rate, during the expansion phase II part. The eCRF should be completed for 
each patient on an ongoing basis and mandatorily after the last visit of Cycle 1. 
Extraordinary meetings may also occur during the conduct of the study in case of any event 
requiring the DSMB recommendations. The DSMB recommendations and meeting minutes 
will be shared immediately with all Investigators/sites. The final recommendations from the 
DSMB will be made available before each EoC meeting during the dose escalation phase 
(see section 4.1.3.3). 
An initial or kick-off DSMB meeting will be performed before the study start to agree on the 
DSMB charter, which will define the quorum that must be in attendance for the validity of the 
meeting, the format and content of the data to be reviewed, the frequency and the modalities of 
the meetings (teleconferences, face-to-face meetings or email exchanges), the timelines and 
format of the minutes. 
The DSMB charter will provide extended details on the composition and the role and 
responsibilities of the DSMB, as well as the organization of the DSMB meetings. 
DSMB recommendations will be forwarded to the IRB/IEC / Competent Authorities on an 
expedited basis only if relevant for the safety of patients. 
13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the ‘Participant information and consent form’ documents, the list of 
investigators document, the insurance documents, the SmPC and the Investigator’s Brochure 
of administered IMPs will be submitted to IRBs/IECs by the investigators or the sponsor in 
accordance with local regulations. 
The study will not start in a centre before written approval by corresponding IRB/IECs 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 1), with the GCP and with the 
applicable regulatory requirements. 


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13.3. Participant information and informed consent 
In any case, the patient (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 from each 
patient before his/her participation in the study. Prior to this, the investigator or his/her delegate 
must inform each patient of the objectives, benefits, risks and requirements imposed by the 
study, as well as the nature of the IMPs. 
The patient will be provided with an ICF in clear, simple language. He/she must be allowed 
ample time to inquire about details of the study and to decide whether or not to participate in 
the study. 
Two original copies per ICF must be completed, dated and signed personally by the patient and 
by the person responsible for collecting the informed consent. The patient will be given one and 
the second will be kept by the investigator. 
If the patient is unable to read, an impartial witness should be present during the entire informed 
consent discussion. The patient 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. 
A copy of the ICF in the language(s) of the country is given in the ‘Participant information and 
consent form’ document attached to the protocol. 
13.4. Modification of the information and consent form 
Any change to the ICF constitutes an amendment to this document and must be submitted for 
approval to the IRB/IEC(s), and if applicable to the Competent Authorities. 
A copy of the new version of the ICF 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 IRB/IEC has been 
obtained and compliance with the local regulatory requirements, with the exception of an 
amendment required eliminating an immediate risk to the study patients. 
Each patient affected by the amendment must complete, date and sign two original copies of 
the new version of the ICF together with the person who conducted the informed consent 
discussion. He/she will receive one signed original amendment to the ICF. 
14. DATA HANDLING AND RECORD KEEPING 
14.1. Study data 
A 21 CFR Part 11-compliant electronic data capture system is going to be used for this study. 
An eCRF is designed to record the data required by the protocol and collected by the 
investigator. 
The eCRF 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 eCRF use 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 patient’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study database. 


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The investigator or the designated person from his/her team agrees to complete the eCRF, at 
each patient visit, and all other documents provided by the sponsor (e.g. documents relating to 
the IMP management, etc.). 
Data recorded directly in the eCRF and considered as source data (see section 4.5) must be 
collected immediately in the eCRF. The other eCRF forms must be completed as soon as 
possible following each visit. 
All corrections of data in the eCRF 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 made the change. 
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. The investigator or co-investigator must attest 
the authenticity of the data collected in the eCRF by entering his/her username and password 
after the last visit of the patient and, as much as possible, either before starting a new level dose 
or at the time of yearly cut-off for DSUR (Development Safety Update Report). 
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 via a request to the sponsor. 
After the last visit of the patient, the investigator or co-investigator must attest the authenticity 
of the data collected in the eCRF by entering his/her username and password. 
After the database lock, the investigator or an authorized member of his/her team will have to 
download from the eCRF an electronic file containing patient data from his/her centre for 
archiving it in the study file (see section 14.3). 
14.2. Data management 
Data is collected via an eCRF and stored in a secured database. 
For data collected in the eCRF, I.R.I.S. Clinical Data Management 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 dedicated providers (central reading ECG, central laboratory, PK, PD 
and PG analysis), I.R.I.S. Clinical Data Management is responsible for data transfer: centralised 
laboratory, central reading centre provide electronic transfer of computerised data to I.R.I.S. 
Clinical Data Management. Data is transferred according to a transfer protocol issued by I.R.I.S. 
data manager. 
I.R.I.S. Medical Review Department 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. 


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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 IRB/IEC it cannot be implemented. All important protocol deviations will 
be recorded and reported in the CSR. 
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. 
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 patient’s data from the eCRF and should keep it in a reliable, secure 
and durable location. The file includes all data and comments reported in the eCRF, 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. 


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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 I.R.I.S. responsibility. The investigator 
commits himself/herself not to publish or communicate data collected in only one 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 CSR. 
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 
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 
12 months after the end of the study. The results will be submitted for publication in scientific 
literature within 18 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. 
With the agreement of the patient, the investigator will inform the patient’s general practitioner 
about his/her patient’s participation in a clinical study. 
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 
investigators or the coordinator or the sponsor, in accordance with local regulations, to the 
IRB/IEC that examined the initial protocol. They can only be implemented after a favourable 
opinion of the IRB/IEC has been obtained, local regulatory requirements have been complied 
with, and the amended protocol has been signed, with the exception of a measure required to 
eliminate an immediate risk to the study patients. 


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When the submission is performed by the investigator or the coordinator, the latter must 
transmit a copy of IRB/IEC new written opinion to the sponsor, immediately upon receipt. 
Furthermore, any 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 I.R.I.S. Pole of Expertise Methodology and Data 
Valorisation in compliance with I.R.I.S. standard operating procedure. 
The sponsor’s representative and the international coordinator must mutually agree on the final 
version. One copy of the final report must be dated and signed by the international coordinator 
and the Director of the Therapeutic Area Oncology and Immuno Oncology. 
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 1 year after the 
end of the clinical trial worldwide. 
If the clinical trial is still ongoing but ended in the European countries, the statistical analysis 
will not be relevant before the end of the study worldwide. Therefore, the CSR, 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 1 year after the end of the clinical trial worldwide. 
17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ supply the investigator with adequate and sufficient information concerning the IMPs 
administered during the study to enable him/her to carry out the study 
­ supply the investigator with investigator’s brochure if the test drug is not marketed 
­ supply the investigator with SmPC, the one best suited to ensure patient safety, and any 
potential updated version during the study: 
 for the marketed IMP, to be appended to Investigator’s brochure (Section 4. Guidance for 
the investigator) 
 for all reference products used in the study 
­ obtain any authorisation to perform the study and/or import licence for the administered 
IMPs that may be required by the local authorities before the beginning of the study 
­ provide the investigator or coordinator annually, or with another frequency defined by the 
local regulations, with a document describing study progress which is to be sent to the 
IRB/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 non-exhaustive measures will be 
implemented: 
 Management of authorisation to access to personal data (eCRF) 
 Identification and authentication measures before accessing personal data (eCRF) 
 Traceability measures for the access to and modification of personal data (eCRF) 
 Secured data transfer 
 Time limit for storing personal data 


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­ handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department, etc.) 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) 
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 S64315 
and study CL1-64315-004 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. 
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 patients. 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 patient screening log and a full identification and enrolment list of each patient 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 patient screening log must be completed from the moment the investigator checks that a 
patient could potentially take part in the study (by assessment of patient 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, etc.) and any other person involved in the study 
for this centre (cardiologist, pharmacist, etc.) 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. 


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17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 
­ 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 measured parameters 
­ to provide any other document required by local regulation (e.g. Food & Drug 
Administration 1572 form) 
­ to send a copy of the IRB/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 patients’ medical 
follow-up/study-related decision process and persons involved in the measurement of main 
assessment criteria). 
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on medicinal products for human use 
 


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19. APPENDICES 
 
Appendix 1: World Medical Association Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 


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8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. 
Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in 
the research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risk, Burdens and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment 
of predic Adams risks and burdens to the individuals and groups involved in the research 
in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 


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Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and 
approval by the committee. After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and conclusions. 
 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 


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Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27. 
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group. 
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 


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31. 
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo, 
or no intervention will not be subject to additional risks of serious or irreversible harm as 
a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
 


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Unproven Intervention in Clinical Practice 
In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorised representative, may use an unproven 
intervention if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 
 


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Appendix 2: Patient Registration Form 
 
 
 
 
PATIENT REGISTRATION FORM / PROTOCOL CL1-64315-004 
Centre: |
|
|
|
| 
 
Please complete Section A and return by fax to Oncology department +33.1.55.72.50.04 or by e-mail to CL1-
64315-004@servier.com 
 
Section A/To be completed after Informed Consent Form signature 
 
Identification of the patient: 
Patient number (= eCRF n°): |__|__|__|__|__| Gender:  Male  Female 
Year of birth: |__|__|__|__| 
Diagnosis of the primary tumour type:…………………………… 
 
Date patient signed Informed Consent Form (dd/mm/yyyy): |__|__| / |__|__| / |__|__|__|__| 
Expected date baseline period completed (dd/mm/yyyy): |__|__| / |__|__| / |__|__|__|__| 
 
Section A completed by:……………………………… 
Please complete Section B and return by fax to Oncology department +33.1.55.72.50.04 or by e-mail to CL1-
64315-004@servier.com 
  
Section B/To be completed after baseline period 
Name of the investigator: ……………………………… 
Fax number: (NA if by email)………………………………….. 
Does the patient comply with all inclusion/exclusion criteria?  Yes  No 
If yes, date of inclusion (dd/mm/yyyy): |__|__| / |__|__| / |__|__|__|__|  
 
Section B completed by:………………………… 
 
Date: |__|__| / |__|__| / |__|__|__|__| 
Signature:……………….…………………………………….. 
 
Section C: Sponsor or its designee 
Identification of the investigator 
Name of the investigator:  
……………………………… 
Fax number  ……………………………… 
 
Identification of the patient 
Patient number: |__|__|__|__|__| 
Gender:  Male  Female 
Year of birth: |__|__|__|__| 
 
Cohort number: |__|__|__| 
 
S64315 LID1: |_2_|_5_| mg 
S64315 LID2: |_5_|_0_| mg 
Full tested dose of S64315: |__|__|__| mg  
 
Section C completed by:…………………………… 
Date: |__|__| / |__|__| / |__|__|__|__| 
Signature:……………….……………………………………. 


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Appendix 3: Patient performance status 
* As published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
 
 
Status 
Karnofsky 
Grade 
Status 
ECOG* - ZUBROD / WHO 
Normal, no complaints; no evidence of disease. 
100 
 
 
0 
Fully active, able to carry on all pre-
disease performance without restriction. 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
90 
 
Normal activity with efforts; some signs or 
symptoms of disease. 
80 
 
 
1 
Restricted in physically strenuous 
activity but ambulatory and able to carry 
out work of a light or sedentary nature, 
e.g., light housework, office work. 
Cares for self; unable to carry on normal activity 
or to do active work. 
70 
 
Requires occasional assistance but is able to care 
for most of his personal needs. 
60 
 
 
2 
Ambulatory and capable of all self-care 
but unable to carry out any work 
activities. Up and about more than 50% 
of waking hours. 
Requires considerable assistance and frequent 
medical care. 
50 
 
Disabled; requires special care and assistance. 
40 
 
 
3 
Capable of only limited self-care,  
confined to bed or chair more than 50% 
of waking hours. 
Severely disabled; hospital admission is 
indicated although death not imminent. 
30 
 
Very sick; hospital admission necessary; Active 
supportive treatment necessary. 
20 
 
 
4 
Completely disabled.  
Cannot carry on any self-care.  
Totally confined to bed or chair. 
Moribund; fatal processes progressing rapidly. 
10 
 
Dead 
0 
5 
Dead 


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Appendix 4: MDRD formula (Levey et al, 2006) 
The reexpressed 4-variable MDRD study equation for GFR, expressed in L/min/1.73m2, with 
serum creatinine (Scr) expressed in mg/dL, is as follows: 
 
GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (age)-0.203 x (0.742 if female) x (1.212 if black) 
 
 








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Appendix 7: Guidance for diarrhoea management (ESMO, 2018) 
Algorithm for diagnostic exams of chemotherapy related diarrhoea: 
 
Algorithm for therapeutic approach: 
 
 


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Appendix 8: Statistical aspects for the dose escalation phase I part and the expansion 
phase II part with an interim analysis for futility 
1. Dose escalation phase I part – ARM A: Operating characteristics of the  Bayesian 
Logistic Regression Model (BLRM) 
1.1. BLRM details – prior specifications 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single-agent parameters for S64315 (α1, β1) and those for azacitidine (α2, 
β2), and the interaction parameter (η12). Derivation of these priors is provided in the following 
subsections. 
1.1.1. Prior for S64315 
The bivariate normal prior for the BLRM parameters (α1, β1) is based on clinical knowledge. 
1.1.1.1. Prior specification 
The Bayesian approach requires the specification of prior distributions for the two model 
parameters: α and β. 
The same weakly informative prior as the one used in CL1-64315-001 study will be used and 
also data from CL1-64315-001 study will be used to enrich this same weakly informative prior 
(see section 1.1.1.2 for details). 
The weakly-informative prior bivariate normal prior for the model BLRM parameters (log(α), 
log(β)) with a reference dose level of 1400mg is obtained as follows: 
­ The median DLT rate at the S64315 reference dose (1400 mg) was assumed to be 20%, i.e. 
mean(log(α1)) = log(0.25) 
­ A doubling in dose was assumed to double odds of DLT, i.e. mean(log(β)) = 0 
­ The standard deviation of log(α) was set to 2, and the standard deviation of log(β) to 1, 
which allows for considerable prior uncertainty for the dose-toxicity profile 
­ The correlation between log(α) and log(β) was set to 0 
Table (1.1.1.1) 1 summarizes these prior parameters. Table (1.1.1.1) 2 describes the prior 
obtained for S64315 agent. The effective sample size (ESS) calculated at each dose level is less 
than 2 patients (weakly-informative prior). 
Table (1.1.1.1) 1 - Prior parameters for bivariate normal distribution of model parameters (𝛂𝛂𝟏𝟏,𝛃𝛃𝟏𝟏) 
Parameters 
Means 
Standard deviations 
Correlation 
log(α1) , log(β1) 
(-1.386, 0.000) 
(2.000, 1.000) 
0 
 
 
 


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Table (1.1.1.1) 2 - Prior distribution summaries derived from priors in Table (8.1.1) 1 
S64315 
dose 
(mg) 
Prior probabilities that 
Pr(DLT) is in interval: 
 
 
Quantiles 
 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
 
Mean 
 
SD 
2.5% 
50% 
97.5% 
ESS1 
25 
0.897 
0.049 
0.054 
0.057 
0.140 
0.000 
0.003 
0.548 
1.755 
50* 
0.874 
0.059 
0.067 
0.070 
0.155 
0.000 
0.006 
0.610 
1.726 
100 
0.841 
0.072 
0.086 
0.087 
0.172 
0.000 
0.011 
0.674 
1.700 
200 
0.795 
0.090 
0.114 
0.111 
0.192 
0.000 
0.022 
0.740 
1.680 
250 
0.776 
0.098 
0.126 
0.122 
0.200 
0.000 
0.028 
0.761 
1.676 
*: Starting dose 
1: Effective Sample Size 
1.1.1.2. Integration of CL1-64315-001 study data as co-data 
Available clinical data from CL1-64315-001 study of the present study will be used to enrich 
the weakly informative prior used for S64315, in a downweighted fashion. The power prior 
obtained after integration of the CL1-64315-001 study data will be used as prior information 
for S64315. 
The CL1-64315-001 study data will be incorporated through down-weighting using the 
following weight “w” (Chen, 2006; Neuenschwander, 2010): 
𝑤𝑤= 
1
1 + 2𝑛𝑛𝜏𝜏2/𝜎𝜎2 
where n is the sample size of external data, σ is the “outcome standard deviation” for one 
observation and τ is the between-study standard deviation. While σ is the standard deviation 
of all external data which include several dose levels, 𝜎𝜎2 can be approximated by variance of 
log(α). For this dose-escalation, σ was then chosen as 2. The between-study standard 
deviation τ was set at 0.25 to correspond to a moderate between-trial variability, as a similar 
frequency of administration of S64315 is planned in the two studies. 
All once a week monotherapy data (CL1-64315-001 study) validated in an End of Cohort 
meeting at the time of assessment of a cohort from combination S64315 and azacitidine will be 
considered to assess this cohort. 
For information, the once a week monotherapy data available as of 26 November 2019, date of 
the last EoC meeting, are presented in Table (1.1.1.2) 1. Of note, based on these data, the highest 
allowed dose of S64315 in monotherapy in the once a week escalation in monotherapy is 300 
mg, the highest dose tested being 500 mg. 
 
 


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Table (1.1.1.2) 1 - CL1-64315-001 study data 
Dose of S64315 
(QW, mg) 
Number of DLT(s) / Number of 
evaluable patients 
50 
1/6 
100 
1/5 
200 
0/5 
250 
0/5 
300 
1/5 
400 
1/3 
500 
3/3 
When accounting for these data, the power prior parameters obtained are presented in 
Table (1.1.1.2) 2. 
Table (1.1.1.2) 2 - Power prior parameters for bivariate normal distribution of model parameters 
Parameters 
Means 
Standard deviations 
Correlation 
log(𝛼𝛼) , log(𝛽𝛽) 
(-0.092, -0.507) 
(0.982, 0.694) 
0.705 
The corresponding power prior distribution is summarized in Table (1.1.1.2) 3. 
Table (1.1.1.2) 3 - Power prior distribution summaries derived from power prior parameters 
in Table (1.1.1.2) 2 
S64315 
dose (mg) 
Prior probabilities that 
Pr(DLT) is in interval: 
Mean 
SD 
Quantiles 
ESS1 
[0, 0.16) 
[0.16, 
0.33) 
[0.33, 1] 
2.5% 
50% 
97.5% 
25 
0.877 
0.112 
0.011 
0.081 
0.075 
0.000 
0.062 
0.277 
12.1 
50* 
0.791 
0.185 
0.025 
0.108 
0.088 
0.001 
0.088 
0.333 
11.4 
100 
0.650 
0.291 
0.059 
0.147 
0.103 
0.006 
0.127 
0.402 
10.7 
200 
0.447 
0.411 
0.143 
0.203 
0.120 
0.026 
0.182 
0.490 
10.2 
250 
0.372 
0.440 
0.188 
0.226 
0.126 
0.038 
0.205 
0.522 
10.0 
* Starting dose level (provided this dose is considered safe (i.e. fulfilling the EWOC criterion) according to the power prior 
obtained by integrating all data from the once-a-week monotherapy study (CL1-64315-001 study) validated in an End of Cohort 
meeting)  
1: Effective sample size 
Note: none of the doses meet the overdose criterion (more than 25% chance of excessive toxicity) with the power prior 
information only. 
The starting dose of S64315 for the combination with azacitidine is 50 mg. This dose is indeed 
considered safe according to the power prior calculated (see Table (1.1.1.2) 3 above). 
1.1.2.  Prior for azacitidine 
The normal prior for the BLRM parameters (α2, β2) of the dose-DLT relationship of azacitidine 
is defined as a weakly-informative prior. The information available on azacitidine (e.g. SmPC) 
have been used to define the prior parameter alpha. As there is only one dose for azacitidine, and 
as the reference dose is equal to this only dose, there is no estimation of β2, then there is now 
only one parameter estimated for this agent. However, a prior has been defined anyway on β2 
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With a reference dose level of 75 mg/m2, the prior parameters are obtained as follows: 
­ The median DLT rate at the azacitidine reference dose (75 mg/m2) was fixed such that the 
mean DLT rate at this dose, with the considered standard deviation, was equal to 8%, leading 
to a median DLT rate of 2.3, i.e. mean(log(α2)) = log (0.023/0.977) (see prior distribution in 
Table (1.1.2) 2) 
­ A doubling in dose was assumed to double odds of DLT, i.e. mean(log(β2)) = 0 
­ The standard deviation of log(α2) was set to 2 which allows for strong prior uncertainty for 
the dose-toxicity profile of azacitidine 
­ The correlation between log(α2) and log(β2) was set to 0 
Table (1.1.2) 1 summarizes these prior parameters. 
Table (1.1.2) 1 - Prior parameters for bivariate normal distribution of model parameters (α2,β2) 
for azacitidine 
Parameters 
Means 
Standard deviations 
Correlation 
log(α2), log(β2) 
(-3.75, 0) 
(2, 1) 
0 
 
Resulting distribution and associated summary statistics are presented in Table (1.1.2) 2. 
Table (1.1.2) 2 - Prior distribution summaries for azacitidine derived from priors in Table (1.1.1.2) 1 
Azacitidine 
dose (mg/m2) 
Prior probabilities that 
Pr(DLT) is in interval: 
 
 
Quantiles 
 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
Mean 
SD 
2.5% 
50% 
97.5% 
ESS1 
75 
0.8574 
0.0795 
0.0631 
0.0803 
0.1404 
5,00E-04 
0.0230 
0.5417 
2.7493 
1: Effective sample size 
1.1.3. Prior for interaction parameter 
A normal prior distribution for the interaction parameter η12 is derived to reflect the current 
uncertainty about the toxicity profile of the combination of S64315 and azacitidine: 
• η12 is normally distributed and centred on 0 (reflecting an assumption of no PK drug-
drug interaction a priori) 
• 97.5th percentile of η12 is selected such that there is a 2-fold increase in odds of DLT due 
to interaction compared to independence at the dose combination (50 mg of S64315, 75 
mg/m2 of azacitidine), allowing for enough uncertainty in case an interaction exists 
Consequently, the mean and standard deviation of the normal prior distribution for η12 turn out 
to be 0 and 9.902 respectively. 
Table (1.1.3) 1 summarizes this prior parameter. Table (1.1.3) 2 shows the prior median and 
95% credible interval for the interaction term exp(η12(d1/d1*)(d2/d2*)) = exp(η12(d1/d1*) (as 
d2=d2*) at all provisional dose level combinations. 
Table (1.1.3) 1 - Prior parameters for normal distribution of model parameters (𝛈𝛈𝟏𝟏𝟏𝟏) 
Parameters 
Means 
Standard deviations 
η12 
0 
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Table (1.1.3) 2 - A priori interaction at the provisional dose levels 
S64315 (mg) 
Azacitidine (mg/m2) 
75 
25 
1 (0.71,1.4) 
50* 
1 (0.5,2) 
100 
1 (0.25,4) 
200 
1 (0.063,16) 
250 
1 (0.031,31) 
*median (95% credible interval) of interaction parameter exp(η12(d1/d1*)(d2/d2*) at dose combination (50 mg of 
S64315, 75 mg/m² of azacitidine) 
1.1.4. Prior for combination 
Combining the priors of the five parameters and including data on S64315 from CL1-64315-
001 study as of 26 November 2019 (power prior), the distribution of the DLT rates for 
provisional dose combinations is summarized in Table (1.1.4) 1. 
The greater effective sample size at lower dose combinations illustrate the greater amount of 
information brought by the CL1-64315-001 study data at these low dose combinations 
(32 patients indeed treated at doses between 50 mg and 500 mg in CL1-64315-001 study, 
among which 21 at 250 mg or below). 
Table (1.1.4) 1 - Distribution summaries derived from Table (1.1.1.2) 3, Table (10.4.4.4) 2, 
Table (10.4.4.4) 3 
S64315 
dose 
(mg) 
Prior probabilities that 
Pr(DLT) is in interval: 
 
 
Quantiles 
 
[0, 0.16) 
[0.16, 
0.33) 
[0.33, 1] 
Mean 
SD 
2.5% 
50% 
97.5% 
ESS1 
 
Azacitidine = 75** mg/m2 
25 
0.661 
0.239 
0.101 
0.156 
0.148 
0.008 
0.112 
0.588 
5.0 
 50* 
0.577 
0.280 
0.143 
0.184 
0.158 
0.012 
0.140 
0.626 
5.0 
100 
0.472 
0.286 
0.241 
0.231 
0.187 
0.017 
0.179 
0.722 
4.1 
200 
0.397 
0.216 
0.387 
0.312 
0.262 
0.012 
0.234 
0.898 
2.1 
250 
0.390 
0.183 
0.427 
0.345 
0.294 
0.008 
0.257 
0.948 
1.6 
*: Starting dose for S64315 (provided this dose is considered safe (i.e. fulfilling the EWOC criterion) according to the power 
prior obtained by integrating all data from the once-a-week monotherapy study (CL1-64315-001 study) validated in an End 
of Cohort meeting) 
**: Starting dose for azacitidine 
1: Effective Sample Size 
Note: bold values indicate dose combinations not meeting the overdose criterion (more than 25% chance of excessive toxicity) 
with the prior information only. 
1.2. Operating characteristics 
1.2.1. Introduction 
This section presents the operating characteristics illustrating the precision of the design in 
estimating the MTD under various assumed true dose-toxicity relationships. 




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1.2.3. Simulation parameters 
For each dose combination-DLT scenario, 5000 clinical trial replications were generated using 
R software version 3.4.1 on a x86-64 architecture on a Linux OS. The MCMC estimation is 
obtained using Rjags R package with 5000 burnin and 10000 iterations on 2 chains (5000 each), 
per scenario. Each clinical replication is numbered from SimulationNumber = 1 to 5000. The 
seed used for data generation is 1234*SimulationNumber and the seed used for MCMC 
estimation is 1 for chain 1 and 2 for chain 2. 
The following trial simulation parameters were used: 
­ Cohort size: 3 
­ Starting dose: 50 mg of S64315 combined to 75 mg/m2 of azacitidine 
The dose allocation rule used in the simulations is the dose having the highest posterior 
probability of the DLT rate falling in the targeted interval [16%, 33%) among the admissible 
doses fulfilling EWOC (note that in practice any admissible dose fulfilling EWOC could be 
recommended). 
1.2.4. Evaluation metrics 
Operating characteristics were reviewed for the simulations to compare the relative 
performance of the design under each true dose-DLT relationship. The following metrics were: 
­ Probability of recommending as the MTD: 
 an undertoxic dose level combination, i.e. a dose combination with true probability of 
DLT in the under-dosing toxicity interval [0%, 16%) (sponsor risk) 
 a targeted dose level combination, i.e. a dose combination with true probability of DLT 
in the targeted toxicity interval [16%, 33%) (correct final decision) 
 an overtoxic dose level combination, i.e. a dose combination with true probability of DLT 
in the excessive toxicity interval [33%, 100%] (patient risk) 
­ Average number of patients per trial exposed at: 
an undertoxic dose level combination, as defined above 
a targeted dose level combination, as defined above 
an overtoxic dose level combination, as defined above 
­ Summary of the total number of patients per trial (average, 1st quartile, median, 3rd quartile) 
­ Average total number of DLTs observed per trial 
1.2.5. Operating characteristics of the design 
Operating characteristics of the final design are reviewed to investigate performance of the 
model under each true dose-DLT scenario. Table (1.2.5) 1 summarises the results from the 
simulations performed according to the rules defined in section 1.2.3. Table (1.2.5) 2 details the 
selection probability of each dose combination in each scenario. 
 
 


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Table (1.2.5) 1 - Summary metrics of the simulations performed 
True 
dose-
DLT 
scenario 
Probability of 
recommending a dose 
combination with true 
P(DLT) 
No MTD 
recommend- 
ation 
Average number of 
patients per trial 
receiving a dose 
combination with true 
P(DLT) 
Average number of patients 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33, 
1] 
Per trial 
(Q1 - Median 
- Q3) 
Experiencing 
a DLT per 
trial 
a 
31.24 
67.02 
NA 
1.74 
12.45 
5.56 
NA 
18.01 
(18 - 18 - 18) 
2.18 
b 
NA 
75.12 
6.04 
18.84 
NA 
9.77 
1.84 
11.61 
(6 - 12 - 15) 
3.15 
c 
NA 
51.18 
20.52 
28.30 
NA 
5.78 
3.94 
9.71 
(6 - 9 - 15) 
3.18 
d 
NA 
1.56 
34.02 
64.42 
NA 
0.38 
6.00 
6.37 
(3 - 6 - 6) 
2.87 
e 
NA 
NA 
25.30 
74.70 
NA 
NA 
5.62 
5.62 
(3 - 3 - 6) 
2.82 
Overall, the BLRM with the specified prior is performing reasonably well in all pre-specified 
scenarios: the performance is good in scenario b and c (the most likely), with a high chance to 
select the right dose while minimizing the probability of overtoxicity, and correct in scenarii a, 
d and e, yet less likely. 
In scenario a, only the highest dose combination falls into the target interval and this dose is 
recommended 67% of the time. By looking more in detail at the probabilities of selection of 
each dose combination in Table (1.2.5) 2, we can see that the dose combinations (200 mg of 
S64315, 75 mg/m2 of azacitidine) – 12% true toxicity rate, and (100 mg of S64315, 75 mg of 
azacitidine) – 9% true toxicity rate, both close to the target interval, are often recommended. 
The scenario a is unlikely as the data from the CL1-64315-001 study already collected are more 
toxic. The minimum number of patients that could trigger a stopping rule is also low (18) so 
that the escalation may stop before reaching the highest dose, even without seeing toxic data. 
In practice the stopping rule could be “ignored” in this situation, to pursue escalation. 
 
 




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1.3.  Hypothetical dose allocation scenarios in early cohorts 
Aside from the overall operating characteristics studied above, the design should make 
reasonable decisions during a study based on the observed DLTs. After completion of a given 
cohort, the dose allocation for the subsequent cohort will depend on the recommendation of the 
model and medical review of all available data.  
Some scenarios to illustrate on-study dose allocation are presented in Table (1.3) 1. These 
scenarios assume that the first cohort will include 5 patients and then each cohort has 3 valuable 
patients and the next recommended dose is based on the dose escalation rules defined in 
section 1.2.3. However, during the study, it may be possible to include 3 to 6 patients by cohort 
and to add new provisional dose levels. 
Table (1.3) 1 - Hypothetical dose allocation scenarios in early cohorts 
Cohort 
Dose 
S64315 
(mg)-
azacitidine 
(mg/m2) 
Nb of 
DLT(s)/Nb 
of patients 
Next 
dose 
level 
(NDL) 
proposed 
(mg) 
Decision 
(S64315-
azacitidine) 
P(Target) 
NDL 
P(Overtox) 
NDL 
Median 
DLT 
rate at 
NDL 
1 
50 - 75 
0/5 
100 - 75 
E-S 
0,2526 
0,0666 
0,1061 
1/5 
100 - 75 
E-S 
0,3941 
0,2246 
0,1996 
2/5 
25 - 75 
D-S 
0,4456 
0,2032 
0,2045 
3/5 
--* 
--* 
--* 
--* 
--* 
4/5 
--* 
--* 
--* 
--* 
--* 
5/5 
--* 
--* 
--* 
--* 
--* 
2a 
(0/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2)) 
100 - 75 
0/3 
200 - 75 
E-S 
0,2020 
0,1312 
0,0926 
1/3 
100 - 75 
S-S 
0,3911 
0,1118 
0,1606 
2/3 
50 - 75 
D-S 
0,4784 
0,0918 
0,1762 
3/3 
50 - 75 
D-S 
0,5436 
0,2295 
0,2356 
2b 
(1/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2)) 
100 - 75 
0/3 
200 - 75 
E-S 
0,2741 
0,2370 
0,1655 
1/3 
50 - 75 
D-S 
0,4874 
0,0969 
0,1793 
2/3 
25 - 75 
D-S 
0,4805 
0,1472 
0,1923 
3/3 
--* 
--* 
--* 
--* 
--* 
2c 
(2/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2)) 
25 - 75 
0/3 
50 - 75 
E-S 
0,5043 
0,1471 
0,1976 
1/3 
25 - 75 
S-S 
0,5178 
0,2217 
0,2265 
2/3 
--* 
--* 
--* 
--* 
--* 
3/3 
--* 
--* 
--* 
--* 
--* 
3a 
(0/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
0/3 in cohort 2 
(100mg – 75 
mg/m2)) 
200 - 75 
0/3 
250 - 75 
E-S 
0,1467 
0,0628 
0,0555 
1/3 
200 - 75 
S-S 
0,3492 
0,2039 
0,1786 
2/3 
100 - 75 
D-S 
0,4881 
0,0966 
0,1811 
3/3 
50 - 75 
D-S 
0,3375 
0,0360 
0,1310 
3b 
(0/5 DLT in 
cohort 1 
(50mg – 75 
100 - 75 
0/3 
200 - 75 
E-S 
0,2958 
0,2294 
0,1707 
1/3 
100 - 75 
S-S 
0,4942 
0,1469 
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mg/m2) and 
1/3 in cohort 2 
(100mg – 75 
mg/m2)) 
2/3 
50 - 75 
D-S 
0,5317 
0,0912 
0,1869 
3/3 
50 - 75 
D-S 
0,5819 
0,2140 
0,2380 
3c 
(0/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
2/3 in cohort 2 
(100mg – 75 
mg/m2)) 
50 - 75 
0/3 
100 - 75 
E-S 
0,4869 
0,2069 
0,2170 
1/3 
50 - 75 
S-S 
0,5663 
0,1178 
0,2011 
2/3 
25 - 75 
D-S 
0,5267 
0,1457 
0,1990 
3/3 
--* 
--* 
--* 
--* 
--* 
3d 
(0/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
3/3 in cohort 2 
(100mg – 75 
mg/m2)) 
50 - 75 
0/3 
50 - 75 
S-S 
0,5564 
0,1101 
0,1975 
1/3 
25 - 75 
D-S 
0,4927 
0,1118 
0,1836 
2/3 
25 - 75 
D-S 
0,5325 
0,2389 
0,2390 
3/3 
--* 
--* 
--* 
--* 
--* 
4a 
(1/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
0/3 in cohort 2 
(100mg – 75 
mg/m2)) 
200 - 75 
0/3 
250 - 75 
E-S 
0,2047 
0,1011 
0,0898 
1/3 
100 - 75 
D-S 
0,4846 
0,0789 
0,1745 
2/3 
100 - 75 
D-S 
0,5720 
0,2320 
0,2447 
3/3 
50 - 75 
D-S 
0,5445 
0,1117 
0,1968 
4b 
(1/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
1/3 in cohort 2 
(100mg – 75 
mg/m2)) 
50 - 75 
0/3 
100 - 75 
E-S 
0,4843 
0,1691 
0,2023 
1/3 
50 - 75 
S-S 
0,5496 
0,1341 
0,2044 
2/3 
25 - 75 
D-S 
0,5300 
0,1804 
0,2135 
3/3 
--* 
--* 
--* 
--* 
--* 
4c 
(1/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
2/3 in cohort 2 
(100mg – 75 
mg/m2)) 
25 - 75 
0/3 
50 - 75 
E-S 
0,5660 
0,1421 
0,2099 
1/3 
25 - 75 
S-S 
0,5374 
0,1734 
0,2120 
2/3 
--* 
--* 
--* 
--* 
--* 
3/3 
--* 
--* 
--* 
--* 
--* 
5a 
(2/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
0/3 in cohort 2 
(25 mg – 75 
mg/m2)) 
50 - 75 
0/3 
100 - 75 
E-S 
0,4483 
0,2222 
0,2140 
1/3 
50 - 75 
S-S 
0,5749 
0,1672 
0,2189 
2/3 
25 - 75 
D-S 
0,5546 
0,2072 
0,2310 
3/3 
--* 
--* 
--* 
--* 
--* 
5b 
(2/5 DLT in 
cohort 1 
(50mg – 75 
mg/m2) and 
1/3 in cohort 2 
25 - 75 
0/3 
50 - 75 
E-S 
0,5732 
0,1849 
0,2246 
1/3 
25 - 75 
S-S 
0,5687 
0,2454 
0,2445 
2/3 
--* 
--* 
--* 
--* 
--* 
3/3 
--* 
--* 
--* 
--* 
--* 


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Overall, the dose recommendation leads to decisions that are in agreement with clinical sense. 
In general, when no DLTs are observed on 3 patients in a dose level, the decision is to increase 
the dose combination. When 1 DLT is observed on 3 patients in a dose level combination, the 
decision is to stay at the current dose level combination. When more than 1 DLT is observed 
on 3 patients in a dose level, the decision is to decrease the dose level. 
2. Expansion phase II part 
2.1. Introduction 
Once the RP2D (MTD or suitable lower dose) has been determined, new patients will be 
enrolled in a two-stage expansion phase II part in three sub-arms A1 and A2. A Bayesian 
interim analysis for futility will be performed at the end of the first stage in each sub-arm. The 
following methodology will be applied for each the three sub-arms. 
During stage 1, the patients will be enrolled and treated at the corresponding RP2D (identified 
during the dose escalation phase I part). One interim analysis for futility will occur when: 
­  All patients included in stage 1 have completed at least four cycles or early discontinued 
­ The CRs reached during this time must be confirmed 
Then, Bayesian analysis will be performed on CR rate. Decision rules will be based on clinical 
threshold defined on the posterior distribution of CR rate (see section 2.3 determination of 
sample size for details). 
According to results of futility interim analysis performed at the end of stage 1, the expansion 
phase II part could be: 
­ Stopped, if results on CR rate are considered futile 
­ Continued if results on CR rate are considered not futile. In that case, one additional cohort 
of patients will be enrolled in stage 2 and treated at the corresponding RP2D 
2.2. 
Methodology 
2.2.1.  Bayesian approach 
The observed response is a binary variable, either a success or failure outcome from the 
administered treatment. With n being the number of observed patients, the number of observed 
responses s, is a binomial variable (n, π), where π is the probability of response. 
Let π, a random variable with the prior distribution Beta(a,b) where a and b>0. The values of a 
and b are fixed at the beginning of the trial (see 2.2.3 Prior specification for details). The mean 
and the variance of the Beta(a,b) distribution are given by E(π)=a/(a+b) and 
Var(π)=ab/((a+b)²(a+b+1)). 
After n patients are included into the trial, the posterior distribution of the probability of 
response, is given by Beta(a+s,b+n-s), with its mean defined by E(π)=(a+s)/(a+b+n). 
(25 mg – 75 
mg/m2)) 
Note: Decision for each agent, E = Escalate, S = Stay, D = Deescalate  
P(Target) NDL: Posterior probability that the true DLT rate for the next recommended dose lies in the 
targeted interval [16%, 33%) 
P(Overtox) NDL: Posterior probability that the true DLT rate for the next recommended dose lies in the 
excessive toxicity interval [33%, 100%] 
*: No doses are considered safe according to the EWOC condition 


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2.2.2. Futility rule 
Stop for futility if there is a high probability that the estimated response rate is lower than a 
minimal response rate threshold.  
That is, P(π ≤ RL|data)>τ where RL is a minimal response rate threshold, fixed before the 
beginning of the trial by clinical development team. 
τ is chosen to be enough restrictive for further stop if flagrant futility is observed, but not too 
much to allow the possibility for activity analysis at study end, by including more patients in 
stage 2. 
2.2.3. Prior specification 
In a Bayesian framework, a prior distribution needs to be defined. In this situation, we choose 
a Jeffreys prior, a non-informative prior distribution, e. g. a=0.5 and b=0.5. 
2.3. Operating characteristics 
2.3.1. Clinical and Statistical assumptions 
According to the information given by the clinical development team, the response rate is 
partitioned as follows: 
• [0%; RL%): No activity on CR rate– results are considered futile 
• [RL%; 100%]: improvement on CR rate – results are not considered futile - one additional 
cohort of patients will be enrolled in stage 2 
The thresholds RL have been defined from literature and given the current information, will be 
the same for the three sub-arms: 
Table (2.3.1) 1 - Choice of response rate threshold RL 
Threshold RL 
References 
20% 
(Schuh, 2017) 
The susmentionned threshold might evolve given the information available before the start of 
phase II part, independently for sub-arms A1 and A2, based on more recent published data if 
available. 
In a Bayesian framework, threshold needs to be defined on the posterior distribution, as 
previously explained for the dose-escalation part appendix. In our case, it is defined as the 
minimum probability to observe less than the fixed threshold CR rate. In our case, if the 
probability of observing CR rate < RL% is over the threshold of 60% (P(CR rate < RL %) > 
60%), we will declare results as futile. 
2.3.2. Simulations parameters 
5000 clinical trials under several scenarios were generated using R software version 3.4.1 on a 
x86-64 architecture on a Linux OS. Several scenarios will be investigated in order to perform 
a sensitivity analysis on the number of patients to enhance the performance of the model. 


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2.3.3. Operating characteristics of the design for stage 1 
2.3.3.1. Probability to stop for futility according to true response rate 
Results of 5000 clinical trials with a true response rate RL were simulated assuming a binomial 
distribution with parameters (𝑛𝑛1, RL) with 𝑛𝑛1 corresponding to the number of patients in stage 1. 
For each clinical trial, the posterior probability of true response rate < RL is compared to the 
threshold of 20%. Then, among the 5000 simulations, the probability to stop for futility at 
interim analysis (i.e. the probability that the posterior probability of true response rate < RL is 
over 60%) is calculated. Results are presented in table below for different value of 𝑛𝑛1. 
Table (2.3.3) 1 - Probability of stopping for futility at RL at the interim 
depending on the number of patients  
Probability (%) stopping for futility at interim  
(P(CR rate < RL %) > 60%) 
True response rate for futility (RL) 
20 pts 
21 pts 
22 pts 
23 pts 24 pts 25 pts 
20 
0,411 
0,368 
0,331 
0,503 
0,466 
0,423 
A minimal number of 23 patients have been fixed to ensure enough evidence for futility analysis 
in a Bayesian framework with a vague prior. 
For clinical trials simulated with true response rate equal to RL, the probability to stop for futility 
at interim is maximized with 𝑛𝑛1= 23 patients in stage 1. These probabilities are equal to 50%. 
Thus, considering 𝑛𝑛1= 23 patients in stage 1 allows to obtain good operating characteristics for 
a futility analysis. 
The same calculations as above were performed for clinical trials simulated with different true 
response rate (from 0% to 100%). Results are presented below for 𝑛𝑛1= 23 patients for stage 1. 
Figure (2.3.3) 1 - Probability to stop for futility during the trial according to the true CR rate (n = 23) 
n =23 
 
 


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According to graphic representations, with 𝑛𝑛1 =23 patients enrolled in stage 1, the probability 
to stop for futility at interim rapidly decreases for true response rate above the threshold RL., 
with a slope of -4.7 at RL. Moreover, probability to stop for futility at interim analysis is less 
than 14% for true response rate equal to RL + 10%. 
2.3.3.2. Minimal number of responders out of 23 patients to continue in stage 2 
Table (2.3.3) 2 - Minimal number of responders out of 23 patients to continue in stage 2 
N 
Observed 
Responses 
Posterior mean 
Probability of the true rate falling 
within 
(N (%)) 
[90% Credible interval] 
[0; 0.20[ 
[0.20; 1] 
23 
  
  
  
3 (13%) 
0.1458 [0.0487; 0.2769] 
0.7930 
0.207 
4 (17.4%) 
0.1875 [0.0754; 0.3296] 
0.6034 
0.3966 
5 (21.7%) 
0.2292 [0.1048; 0.3797] 
0.3980 
0.602 
6 (26.1%) 
0.2708 [0.1361; 0.4277] 
0.2253 
0.7747 
The futility decision will be overpassed if we observe at least 5 responders out of 23 patients 
during stage 1. In that case (5 responders/23 patients), the posterior probability for true response 
rate to be ≥20% is equal to 60% which provides enough evidence for non-futility of the d in the 
context of interim analysis. 
Thus, according to all analyses presented above, with n 1 = 23 patients in stage 1, the operating 
characteristics of the design are considered sufficient and do not justify a further increase in the 
sample size for stage 1. 
2.3.4. Operating characteristics of the design for stage 2 
In case of no futility decision at interim analysis, one additional cohort of patients will be 
enrolled in stage 2 and treated at the corresponding RP2D. In the following sections, the 
operating characteristics of the design will be checked in case of enrolment of 27 additional 
patients in stage 2 (𝒏𝒏𝟐𝟐 = 27), giving an overall sample size of n=𝒏𝒏𝟏𝟏+ 𝒏𝒏𝟐𝟐 = 50 patients for the 
expansion phase II part. 
2.3.4.1. Operating characteristics according to true response rate 
The same simulation analyses as the ones performed for stage 1 have been done. 
Results of 5000 clinical trials with a true response rate RL (same as stage 1) were simulated 
assuming a binomial distribution of parameters (n, RL), with 𝒏𝒏= 𝟓𝟓𝟓𝟓, corresponding to the 
overall number of patients of expansion phase II part, e.g. first 23 patients included at stage 1 
and then 27 more. The posterior probability of true response rate > RL is compared to different 
thresholds (70%, 80%), for the overall number of subject 50. Then, among the 5000 
simulations, the probability that the posterior probability of true response rate > RL is over the 
threshold is calculated, with RL=20%. Results are presented in table below. 
Table (2.3.4.1) 1 - Probability of having a posterior probability of true response rate RL 
over a threshold Y 
 
Overall number of subject 
Probability (%) for P(CR >20) > Y % at study end 
Y=70% 
Y=80% 
50 
24.7 
17.0 


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Considering a threshold of 70% (respectively 80%), there is 25% probability (respectively 17% 
probability) that the posterior probability of true response rate be greater than RL, for clinical 
trials simulated with a true response rate equal to the futility boundary RL.  
Same calculations were performed for clinical trials simulated with different true response rates 
(from 0% to 100%). Results are presented below for n=50 patients and for 70% boundary. 
Figure (2.3.4) 1 - Probability for P(CR rate > RL) > 70% at study end according to the true CR rate 
 
According to graphic representations, with 𝑛𝑛= 50 patients for the expansion phase II part, the 
chance that the posterior probability of true response rate be greater than RL, rapidly increases 
for true response rate above the threshold RL: these probabilities reach 80% for true response 
rate equal to RL + 10%. 
According to these results, we consider that 50 patients for expansion phase II part provide 
enough evidence for activity. 
2.3.4.2 Justification based on precision of the estimate 
Moreover, the length of the credibility interval has also been checked with 50 patients included 
for the expansion phase II part per sub-arm. 
50 patients enrolled in the expansion phase II part per sub-arm ensure a maximal length of the 
90% credibility interval on the posterior distribution (i.e. a minimal precision) of 23% around 
the estimated response rate at each sub-arms end. 
2.3.4.3. Conclusion for overall number of patients in expansion phase II part 
Thus, according to all analyses presented above, n = 50 patients for each sub-arm of the 
expansion phase II part allow to have sufficient operating characteristics of the design for 
activity assessment, so N=150 overall for the expansion phase II part. 
 
 


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Appendix 9: Local modification of the clinical study protocol 
 
 
 
FINAL VERSION DATE: 
14 December 2020 
COUNTRY(COUNTRIES) CONCERNED: 
FRANCE 
 
 
NATURE OF MODIFICATIONS 
 
- 
Paragraphs impacted: Synopsis – Non screening criteria, 5.2.2. General criteria 
 
- 
Amended text: 
 
SYNOPSIS 
[…] 
Non screening criteria 
[…] 
9a. Unlikely to cooperate in the study or legally incapacitated person under guardianship or trusteeship or judicial 
protection. 
 
 
5.2.2. General criteria 
[…] 
9a. Unlikely to cooperate in the study or legally incapacitated person under guardianship or trusteeship or judicial 
protection. 
 
 


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Appendix 10: Instructions to investigator for handling data rights requests 
 
DATA PROTECTION / GDPR (General Data Protection Regulation of 27 April 2016 
n°2016/679)–  
INSTRUCTIONS 
TO 
INVESTIGATOR 
FOR 
HANDLING 
DATA 
RIGHTS 
REQUESTS 
In the framework of a research study/clinical trial, a participant to the study may exercise his/her 
rights, i.e. may ask I.R.I.S. (as data controller) for:  
• access to his/her data 
• rectification of inaccurate/incomplete information 
• restriction of processing of data 
• objection to processing of data 
• data portability (receiving his/her data in a readable format) 
 
In accordance with the Informed Consent Form and information notice provided to participant, 
we requested participant to contact you first for exercising their rights.  
Request for exercise of rights: 
• has to be a written one (either originating from an (e)-mail from a participant or from request 
 
expressed orally to you and put in written) 
• has to be sent by you by e-mail or by mail to I.R.I.S. (as data controller) to central address 
 
dataprivacy@servier.com or local Servier address as mentioned in ICF/information notice 
 
provided/available  
 
DO 
Instructions to be followed by you 
DON’T 
What you should not do 
E-mail title: Data protection rights 
Do not forward participant e-mail (if 
applicable) 
Study name/number 
 
Participant number 
No information regarding participant 
identity:  
No participant’s name, e-mail address, 
participant’s signature 
As soon as possible without exceeding a week  
 
 


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I.R.I.S. and INVESTIGATOR responsibilities  
GDPR requirement:  
It is mandatory for I.R.I.S. as data controller to provide an answer to 
participant/volunteer within 1 month following the request (article 12 of GDPR) 
Clinical trials requirements:  
It is prohibited for I.R.I.S. as a sponsor to know the identity of the 
participants/volunteer participating to studies  
 
 
I.R.I.S. responsability 
Investigator responsability 
Forward/inform I.R.I.S. of the 
request 
 
YES 
Timelines  
Answer within 1 month 
once expressed by the 
participant 
 
Request: transmitted to 
I.R.I.S. as soon as expressed 
by the participant 
 
Answer: transmitted by you 
to participant as soon as sent 
by I.R.I.S.  
Answer the request 
YES 
 
 

SAP_001.pdf: 
 S 64315 
CL1-64315-004 – Statistical Analysis Plan – Final V1.0 
 
Document title 
STATISTICAL ANALYSIS PLAN 
 
 
 
Study official title  
Phase I/II, international, multicentre, open-label, non-
randomised, non-comparative study evaluating the safety, 
tolerability and clinical activity of intravenously 
administered S64315, a selective Mcl-1 inhibitor, in 
combination with azacitidine in patients with 
acute myeloid leukaemia (AML) 
 
 
Test drug code 
S64315 
 
 
Indication 
Acute Myeloid Leukaemia (AML) 
 
 
Development phase 
Phase I/II 
 
 
Protocol code 
CL1-64315-004 
 
 
EudraCT Number 
2019-004896-38 
 
 
Universal Trial Number 
Not applicable 
 
 
Sponsor 
I.R.I.S. 
 
 
Date of the document 
25th September 2023 
 
 
Version of the document 
V1.0 
 
 
 
CONFIDENTIAL 
 
 
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Follow up of versions 
Version Release date 
(dd/mm/yyyy) Key modifications 
Impact 
0.1 
20/02/2023 
Creation 
No impact 
0.2 
07/03/2023 
Implementation of sponsor’s 
comments 
No impact 
0.3 
13/04/2023 
Implementation of sponsor’s 
comments 
No impact 
0.4 
26/04/2023 
Implementation of sponsor’s 
comments 
No impact 
1.0 
25/09/2023 
Finalization of version 1 with 
implementation of sponsor’s 
comments 
No impact 
 
 
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Table of contents 
1. INTRODUCTION ............................................................................................................. 11 
1.1. Study objectives .............................................................................................................. 11 
1.2. Study endpoints ............................................................................................................... 12 
1.3. Study design .................................................................................................................... 12 
1.3.1. Dose administration schedule and escalation ............................................................... 12 
1.3.2. Study plan ..................................................................................................................... 14 
1.3.3. Type of randomisation .................................................................................................. 17 
1.4. Determination of sample size ......................................................................................... 17 
2. ANALYSIS SETS AND SUBGROUPS ........................................................................... 17 
2.1. Analysis sets and subgroups ........................................................................................... 17 
3. STATISTICAL METHODS ............................................................................................. 18 
3.1. General considerations .................................................................................................... 18 
3.2. Disposition and baseline characteristics ......................................................................... 18 
3.2.1. Disposition of patients .................................................................................................. 18 
3.2.2. Protocol deviations ....................................................................................................... 19 
3.2.3. Analysis sets and subgroups ......................................................................................... 19 
3.2.4. Demographic data and other baseline characteristics ................................................... 19 
3.2.4.1. 
Demographic data .................................................................................................... 19 
3.2.4.2. 
Pregnancy test .......................................................................................................... 19 
3.2.4.3. 
Disease history ......................................................................................................... 19 
3.2.4.4. 
Previous therapies .................................................................................................... 20 
3.2.4.5. 
Signs and symptoms related to AML ...................................................................... 21 
3.2.4.6. 
Clinical laboratory baseline evaluation ................................................................... 21 
3.2.4.7. 
Initial disease assessments ....................................................................................... 21 
3.2.4.8. 
Medical and surgical history not related to AML .................................................... 21 
3.2.4.9. 
Vital signs and clinical examination at baseline ...................................................... 21 
3.2.4.10. Centralised ECG at baseline .................................................................................... 22 
3.2.4.11. LVEF at baseline ..................................................................................................... 22 
3.2.4.12. Chest X-Ray ............................................................................................................. 22 
3.2.4.13. TLS prevention ........................................................................................................ 22 
3.2.5. Treatments of patients .................................................................................................. 22 
3.2.5.1. 
Extent of treatment exposure and treatment compliance ......................................... 22 
3.2.5.2. 
Concomitant treatments ........................................................................................... 24 
3.2.6. Other observations related to patient follow-up ........................................................... 24 
3.3. Efficacy analysis ............................................................................................................. 24 
3.4. Safety endpoints .............................................................................................................. 24 
3.4.1. Dose limiting toxicity ................................................................................................... 25 
3.4.2. Adverse events.............................................................................................................. 25 
3.4.3. Death............................................................................................................................. 25 
3.4.4. Clinical laboratory evaluation ...................................................................................... 25 
3.4.5. Vital signs and clinical examination............................................................................. 28 
3.4.6. Centralised ECG ........................................................................................................... 28 
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3.4.7. LVEF ............................................................................................................................ 28 
3.5. Exploratory analysis ....................................................................................................... 29 
3.6. Interim analysis ............................................................................................................... 29 
4. APPENDICES .................................................................................................................... 29 
4.1. General analytic definitions ............................................................................................ 29 
4.1.1. Expressions ................................................................................................................... 29 
4.1.2. First and last IMP intakes dates .................................................................................... 30 
4.1.3. Value prior to treatment / under treatment ................................................................... 31 
4.1.4. General duration derivation and conversion ................................................................. 31 
4.1.5. Analysable value .......................................................................................................... 31 
4.1.6. Management of other dates .......................................................................................... 32 
4.2. Specific analytic definitions and data handling conventions .......................................... 33 
4.2.1. Study patients: Disposition, baseline characteristics and follow-up ............................ 33 
4.2.1.1. 
Disposition of patients ............................................................................................. 33 
4.2.1.2. 
Protocol deviations .................................................................................................. 33 
4.2.1.3. 
Demographic data and other baseline characteristics .............................................. 33 
4.2.1.3.1. Demographic data .................................................................................................. 33 
4.2.1.3.2. History of AML ..................................................................................................... 33 
4.2.1.3.3. Medical history and surgical or medical procedures history other than AML ...... 34 
4.2.1.3.4. Signs and symptoms related to AML or prior therapies received for studied 
disease ................................................................................................................... 34 
4.2.1.3.5. Previous therapies for AML .................................................................................. 34 
4.2.1.3.6. Initial disease assessment ...................................................................................... 35 
4.2.1.4. 
TLS prevention ........................................................................................................ 36 
4.2.1.5. 
Extent of exposure and treatment compliance ......................................................... 36 
4.2.1.6. 
Concomitant treatments ........................................................................................... 41 
4.2.1.7. 
Other observations related to patient follow-up ...................................................... 45 
4.2.2. Efficacy......................................................................................................................... 45 
4.2.3. Safety ............................................................................................................................ 45 
4.2.3.1. 
Dose Limiting Toxicity (DLT) ................................................................................ 45 
4.2.3.2. 
Adverse events ......................................................................................................... 46 
4.2.3.3. 
Death ........................................................................................................................ 49 
4.2.3.4. 
Clinical laboratory evaluation .................................................................................. 49 
4.2.3.5. 
Vital signs, clinical examination and other observations related to safety .............. 52 
4.2.3.5.1. Vital signs and clinical examination ..................................................................... 52 
4.2.3.5.2. Electrocardiogram ................................................................................................. 53 
4.2.3.5.3. LVEF ..................................................................................................................... 54 
4.2.4. Biomarkers ................................................................................................................... 54 
5. REFERENCES .................................................................................................................. 55 
 
 
 
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List of tables 
Table (1.3) 1 - Provisional dose levels of S64315 ................................................................... 13
Table (2.1) 1 - Minimum number of S64315 and azacitidine doses to meet minimum 
exposure until the end of cycle 1 .............................................................................................. 18
Table (3.4.4) 1 – Gradable parameters ..................................................................................... 26
Table (3.4.4) 2 – Non Gradable parameters ............................................................................. 27
Table (4.1.2) 1 - Substitution rules of IMP intake dates .......................................................... 30
Table (4.1.3) 1 - Time frame .................................................................................................... 31
Table (4.1.5) 1 - Definition of analysable value ...................................................................... 31
Table (4.1.6) 1 - Substitution rules of death date ..................................................................... 32
Table (4.1.6) 2 - Substitution rules of dates if no specific management is defined ................. 32
Table (4.1.6) 3 - Substitution rules of dates and times if no specific management is 
defined ...................................................................................................................................... 32
Table (4.2.1.6) 1 - Substitution rules of concomitant treatments intake dates ......................... 42
Table (4.2.1.6) 2 - Substitution rules of further anti-leukemic therapy intake dates ............... 44
Table (4.2.3.1) 1 –Toxicity criteria .......................................................................................... 45
Table (4.2.3.2) 1 – Emergence of adverse events in case of missing severity/grade (if 
any) ........................................................................................................................................... 48
Table (4.2.3.2) 2 – Substitution rules of AE dates ................................................................... 48
Table (4.2.3.2) 3 - Substitution rules of recovery date ............................................................. 49
Table (4.2) 4 - Definition of CTCAE grade - Version 5.0 - Gradable parameters  ................. 50
List of figures 
Figure (1.3.2) 1 - Study plan for S64315 administration schedule in combination with 
azacitidine (dose escalation phase I part – Arm A) .................................................................. 16
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List of abbreviations 
%: Percent 
ADME : Absorption Distribution Metabolism Excretion 
AE : Adverse Event 
ALP : ALkaline Phosphatase 
ALT : ALanine aminoTransferase 
AML : Acute Myeloid Leukaemia 
aPTT : activated Partial Thromboplastin Time 
AST : ASpartate aminoTransferase 
ATC: Anatomical Therapeutic Chemical 
AZA : Azacitidine 
Bcl-2 : B-cell lymphoma 2 protein 
BLRM : Bayesian Logistic Regression Model 
BM : Bone Marrow 
BNP : Brain Natriuretic Peptide 
bpm : beats per minute (heart rate unit) 
BR : Best Response 
C : Cycle 
CLcr : Creatinine CLearance 
CPK : Creatine Phosphokinase 
CPK-MB : Creatine PhosphoKinase Myocardial Band 
CR : Complete Remission 
CRi : Complete Remission with incomplete haematologic recovery 
CSR : Clinical Study Report 
Cx : Cycle x 
D : Day 
DBP : Diastolic Blood Pressure 
DI : Dose Intensity 
DLT : Dose Limiting Toxicity 
DLTES : Dose-Limiting Toxicity Evaluable Set 
DNA : Deoxyribonucleic Acid 
e.g. : Exempli gratia (for example) 
ECG : ElectroCardioGram 
ECOG : Eastern Cooperative Oncology Group 
eCRF : Electronic Case Report Form 
EMA : European Medicines Agency 
EoC : End of Cohort 
EoT : End of Trial 
EWOC : Escalation With Overdose Control 
FAB: French-American-British 
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FU : Follow-Up 
G/L : Giga (109) per litre 
GGT : Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
HbcAb : B virus core antibody 
HbsAb : B virus surface antibody  
HbsAg : Hepatitis markers B virus surface antigen  
HBV : Hepatitis B Virus 
HCV : Hepatitis C Virus 
HDL : High-Density Lipoprotein 
HEV : Hepatits E Virus 
HMA : HypoMethylating Agents 
HR : Heart Rate 
i.e. : id est (that is) 
ICF : Informed Consent Form 
ICH : International Conference on Harmonisation 
IME : Independent MedicalExam 
IMP : Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial i.e. S64315 and azacitidine 
INR : International Normalized Ratio 
I.R.I.S. : Institut de Recherches Internationales Servier 
IS : Included Set 
IU : International Unit 
IV : IntraVenous (route) 
kg : Kilogram 
LDH : Lactate DeHydrogenase 
LDL : Low-Density Lipoprotein 
LID : Lead-In Dose 
LLN : Lower Limit Normal of reference range 
LVEF : Left Ventricular Ejection Fraction 
Max: Maximum 
MCL1 : HGNC Approved Gene Symbol for Myeloid Cell Leukaemia 
Sequence 1 
Mcl-1 : Induced myeloid leukaemia cell differentiation protein 
MDS : MyeloDysplastic Syndrome 
MDRD_GFR : Modification of Diet in Renal Disease Glomerular Filtration Rate 
MedDRA : Medical Dictionary for Regulatory Activities 
mg : Milligram 
min : Minimum 
mL : Millilitre 
MLFS : Morphologic Leukaemia-Free State 
mmHg : Millimetres of mercury 
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MPN : myeloproliferative neoplasms  
MRD : Minimal (measurable) Residual Disease 
msec: Milliseconds 
MTD : Maximum Tolerated Dose 
N : Number 
NA : Not Applicable 
NAE : Number of Adverse Events 
NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events  
NPD: Number of Protocol Deviations 
PB : Periferal Blood 
PCR : Polymerase chain reaction 
PD : PharmacoDynamics 
PDI : Planned Dose Intensity 
PG : PharmacoGenomics 
PK : PharmacoKinetics 
PR : Partial response 
PT : Preferred Term 
PV : PharmacoVigilance 
QTc : QT interval corrected for heart rate 
QTcF : QTc interval corrected with Fridericia’s formula 
QW : Once Weekly 
Q1 : First Quartile 
Q3 : Third Quartile 
RBC : Red Blood Cells 
RDI : Relative Dose Intensity 
RNA : Ribonucleic acid 
RP2D : Recommended Phase II Dose 
SAE : Serious Adverse Event 
SAP : Statistical Analysis Plan  
SBP : Systolic Blood Pressure 
SC SubCutaneous (route) 
SD : Standard Deviation 
SI : Standard International  
SOC : System Organ Class 
SS : Safety Set 
TEAE : Treatment Emergent Adverse Event 
TLG : Tables, Listings and Graphs 
TLS : Tumour Lysis Syndrome 
TPN : Total parenteral nutrition 
TSH : Thyroid Stimulating Hormone 
ULN : Upper Limit Normal of reference range 
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WBC : White Blood Cells 
WHO : World Health Organization 
WHODD : World Health Organization, Drug Dictionary 
WV : Withdrawal Visit 
 
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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 V5.0 dated 14th of October 2022. 
The shells for Tables, Listings and Graphs (TLG) are described in a separate document. 
 
The study data will be analysed and reported in the Primary abbreviated Clinical Study Report 
(CSR) once the study is terminated (at the end-of-study, defined as the date of the last follow-
up of the last patient, including a phone contact, or the date of the last contact attempt if the last 
patient is declared lost to follow-up). A statistical data review will be conducted prior to 
database lock. A limited number of outputs will be produced for the purpose of reviewing the 
data prior to authorizing the database lock. 
The final analysis for the abbreviated CSR will be performed (and so the database locked) as 
soon as all safety data are available, and all the mandatory steps required for database lock have 
been performed. 
Of note, this SAP does not cover the pharmacokinetic and pharmacodynamic profiling data 
analyses described in the study protocol. These analyses are covered in separate analysis plans 
written by I.R.I.S. Clinical Pharmacokinetics and Technologie Servier, respectively.  
Given the abbreviated nature of the CSR, this SAP will cover the disposition, demographics 
and baseline characteristics of the study sample, the extent of exposure and treatment 
compliance to the investigational medicinal products (IMP)s, and the safety profile of the IMPs. 
Efficacy of IMPs and other observations related to patient follow-up will not be analysed. 
1.1. Study objectives 
The primary objective of the study is to determine the safety profile (including dose-limiting 
toxicity (DLT) and maximum tolerated dose (MTD)) and tolerability of S64315 in 
combination with azacitidine in patients with AML. 
The secondary objectives (not addressed by this SAP) are: 
- 
To determine the pharmacokinetics (PK) profile of S64315 and azacitidine administered in 
combination, and potential metabolites. 
- 
To evaluate anti-leukemic activity of S64315 in combination with azacitidine. 
The exploratory objectives of the study (not addressed by this SAP) are: 
- 
To assess the minimal (measurable) residual disease (MRD) and clonal evolution after 
treatment with the combination of S64315 with azacitidine. 
- 
To evaluate the pharmacodynamic (PD) profile of S64315 in combination with azacitidine 
in relation to: 
➢ The biological activity (target engagement). 
➢ The relationship between the expression level of B-cell lymphoma 2 protein (Bcl-2) 
family members (in blood, and bone marrow samples) and the anti-leukemic activity. 
➢ The relationship between the anti-leukemic activity, karyotypes and AML associated 
genes mutations or dysregulations. 
- 
To explore PK/PD relationship for safety and efficacy. 
- 
To explore relationship between the deoxyribonucleic acid (DNA) polymorphism for 
proteins involved in the absorption distribution metabolism excretion (ADME) and the 
variability of PK parameters. 
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1.2. Study endpoints 
The endpoints for the primary objective are: 
- 
The incidence of DLT(s) starting from the lead-in dose (LID) period to the end of each cycle 
of treatment of S64315 in combination with azacitidine. 
- 
The incidence and severity of adverse events (AEs) and serious adverse events (SAEs) 
according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 5.0. 
- 
The recording of any change or addition of a new concomitant treatment. 
- 
The laboratory tests: haematology with differential, blood biochemistry, thyroid function, 
blood coagulation, urinary analysis, hepatitis markers, Tumour Lysis Syndrome (TLS) 
monitoring, cardiac markers follow up. 
- 
The complete physical examination, Eastern Cooperative Oncology Group (ECOG) 
performance status and vital signs measurements. 
- 
The electrocardiogram (ECG) parameters and cardiac function assessment. 
- 
The left ventricular ejection fraction (LVEF). 
- 
The dose interruptions, reductions and dose intensity. 
1.3. Study design 
The study CL1-64315-004 is an international, multicentre, non-randomised, non-comparative, 
open label, phase I/II study of S64315 and azacitidine administered in combination, conducted 
in patients with AML. 
This study was originally designed in two phases: Phase I for dose escalation and Phase II for 
dose expansion. Furthermore, the dose escalation phase I part was further planned to have 2 
arms: Arm A evaluating the combination of S64315 with azacitidine (see Figure (1.3.2) 1), and 
Arm B evaluating the triplet regimen of S64315 with azacitidine and a Bcl-2 inhibitor. 
However, Phase I - Arm B and Phase II for dose expansion will not be conducted. 
1.3.1. 
Dose administration schedule and escalation 
The initial schedule (see Figure (1.3.2) 1) will consist of a lead-in period followed by 28-day 
cycles when S64315 will be administered in combination with azacitidine. S64315 will be 
administered via intravenous (IV) infusion over at least 2 hours once every week, azacitidine 
will be administered via subcutaneous (SC) injection once daily for 7 consecutive days. 
The schedule will be as follows: 
- 
A 2-week LID period with S64315 fixed LID1 of 25 mg on day -13 (D-13) and S64315 
fixed LID2 of 50 mg on D-6, followed by 
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- 
28-day cycles (Cx) of combination treatment period with S64315 administered on CxD2, 
CxD9, CxD16 and CxD23, and 75 mg/m² of azacitidine administered daily for 7 days from 
CxD1 to CxD7 followed by a rest period of 21 days. 
On days of concomitant administration of S64315 and azacitidine (CxD2), azacitidine should 
be administered 2 hours (±10 min) prior to S64315. The starting dose of S64315 after the lead-
in period will be 50 mg. A panel of doses (see Table (1.3) 1 from 25 mg (-1) and up to 250 mg 
could be explored according to the dose escalation process of the Bayesian Logistic Regression 
Model (BLRM).  
During the dose escalation phase, at each new dose level, the IMPs will be firstly administered 
to one patient. If no medically important or life-threatening toxicity occurs during a 1 week 
observation period, the subsequent patients will be allowed to start treatment without further 
delays between subsequent patients. The dose increase between two dose levels will be guided 
by the observed toxicities. 
An adaptive BLRM with overdose control (EWOC) will be used to guide the dose escalation 
of S64315 in combination with azacitidine. The dose escalation will only concern S64315. The 
purpose of the dose escalation phase I part is to determine the safety profile, the MTD, the DLTs 
and the recommended Phase II Dose (RP2D) in patients with relapsed/refractory AML. All 
available data on DLTs (assessed from the LID period and up to the end of cycle 1) will be used 
for updating the model. Before making a decision regarding dose escalation, the minimum 
number of patients required from a cohort must have been treated with one cycle of the 
combination and be fully evaluable for treatment-related toxicities according to the minimum 
requirements for inclusion in the Dose-Limiting Toxicity Evaluable Set (DLTES). If a patient 
is not eligible for inclusion in the DLTES, this patient must be replaced.  
A maximum of 6 DLT-evaluable patients may be initially enrolled at a new dose level, and a 
minimum of 3 DLT-evaluable patients must be treated at a given dose level in order to begin 
treatment of patients at a new, higher dose level. To better characterize the safety, tolerability, 
PK, PD, or preliminary clinical activity of S64315 in combination with azacitidine, more than 
6 DLT-evaluable patients may be treated in a cohort. If the starting dose of the combination is 
not well tolerated, a dose level -1 will be considered. Intermediate doses may be tested, if 
needed. A minimum of 6 DLT evaluable patients must have been evaluated at the dose 
considered to be the MTD, and before treating patients with this dose in the Phase II part of the 
study. 
Table (1.3) 1 - Provisional dose levels of S64315 
 
Dose level      
     Proposed dose* 
 Increment from previous dose 
  
   -1** 
25 mg 
-50% 
  
1 
50 mg 
Starting dose 
  
2 
100 mg 
100% 
  
3 
200 mg 
100% 
  
4 
250 mg 
25% 
  
*It is possible for additional and/or intermediate dose levels to be added during the course of the study  Cohorts can be added at any dose 
level below the MTD in order to better understand safety, PK or PD  
**No dose reduction below dose level -1 is permitted for this study  
 
Before testing a new dose level during the dose escalation phase, an end of cohort (EoC) 
meeting between the Sponsor (Centre for Therapeutic Innovation Oncology, Medical Safety 
Leader, Methodology Department and Clinical Pharmacokinetics department), the coordinator 
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and the investigators will take place to discuss the toxicities in terms of DLTs, safety data, the 
PK and available PD, and the preliminary efficacy data observed in all patients. 
Of note, the dose escalation part was stopped by a joint decision from Servier and Novartis by 
taking into account the model estimations and a global assessment of the safety, PK, PD and 
preliminary activity data. No intra-patient dose escalation and no expansion part will be 
conducted for this study.  
1.3.2. 
Study plan 
The study start is defined as the date of the first visit of the first patient, corresponding to 
informed consent form (ICF) signature. It will be divided into the following periods for each 
patient of Arm A: 
- Screening visit 
The screening eligibility criteria will be checked after the patient informed consent is obtained. 
- Inclusion period 
The inclusion and exclusion criteria will be checked. The inclusion period can last up to 15 
days before starting the LID period. The patient is included when he/she has met all the 
inclusion criteria. 
- S64315 lead-in dose period 
The lead-in dose period will last 2 weeks. S64315 LID1 will be administered on D-13 at 25 
mg and LID2 on D-6 at 50 mg. LID1 and LID2 doses will be fixed all along the study. 
- Combination treatment period 
A treatment cycle will consist of 28 days for patients treated with S64315 in combination with 
azacitidine during the dose escalation phase I part: 
- 
Weekly schedule for S64315 on CxD2, CxD9, CxD16 and CxD23. 
- 
Daily schedule for azacitidine from CxD1 to CxD7 followed by a 21-day rest period. 
The planned duration of combination treatment is until disease progression, unacceptable 
toxicity, treatment failure (defined as failure to achieve complete remission (CR), complete 
remission with incomplete haematologic recovery (Cri), partial response (PR), or morphologic 
leukaemia-free state (MLFS) after at least 6 cycles of study treatment) or patient/physician 
decision. In case of myelosuppression within the context of non-active AML, a 4-week 
interruption of administration of one or both IMP(s) will be allowed for bone marrow recovery 
at the investigator’s discretion after discussion and approval from the Sponsor. If the patient is 
benefiting from the study treatment according to the investigator’s judgement and if it is in the 
patient’s best interest to continue the combination of S64315 with azacitidine, the patient may 
remain on study treatment. In case the patient becomes eligible for transplant, patient’s 
treatment discontinuation should be left at the investigator’s decision. 
- Withdrawal visit (WV):  
Up to 28 days after the last dose of IMP 
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- Post-withdrawal follow-up 
After the withdrawal visit, a contact or telephone call will be done for the patients: 
- 
Every 3 months (±15 days) from the WV and up to 6 months, except in case of consent 
withdrawal for the dose escalation phase I part. 
- End of Trial (EoT) 
The EoT is defined as the date of the last follow-up of the last patient (including a phone 
contact), or the date of the last contact attempt if the last patient is declared lost to follow-up. 
 
 
 
 
 
 
 
 
 
 
 
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Figure (1.3.2) 1 - Study plan for S64315 administration schedule in combination with azacitidine (dose escalation phase I part – Arm A) 
 
 
  
S64315 infusion on D-13, D-6, CxD2, CxD9, CxD16, CxD23 
AZA: azacitidine 
Azacitidine administration from CxD1 to CxD7 
D: day 
PK: pharmacokinetic measurements 
FU: post-withdrawal follow-up 
PD: pharmacodynamics measurements 
LID: Lead-in dose 
PG: optional pharmacogenomics measurements 
QW: Once Weekly 
WV: withdrawal visit 
W: week 
 
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1.3.3. 
Type of randomisation 
The assignment of a patient to a particular cohort will be coordinated by the Sponsor. No 
randomisation will be performed in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4. Determination of sample size 
No formal statistical power calculations to determine sample size were performed for this 
study. Overall, a maximum of 180 patients will be enrolled in the dose escalation phase I part 
of Arm A (up to 30 patients) followed by sub-arms A1and A2 (50 per sub-arms, up to 150 
patients overall). However, due to the stop of the dose escalation phase, the expansion part to 
sub-arms A1 and A2 will not be conducted. 
2. ANALYSIS SETS AND SUBGROUPS 
2.1. Analysis sets and subgroups 
- Screened Set: 
All patients who signed the ICF, whether they are included or not at the end of the screening 
period. 
- Included Set (IS): 
All patients who have signed the ICF, whose eligibility was confirmed at the end of the 
screening period, and who were included in the dose escalation phase I part of the study. 
- Safety Set (SS): 
All patients who have signed the ICF and who received at least one dose of IMP (S64315 or 
azacitidine) during dose escalation phase I part of the study. It will be used for all safety 
analyses. 
For the safety analysis, patients will be analysed according to the treatment combination and 
dose level received at C1D1 (for azacitidine) and C1D2 (for S64315). Patients who only 
received LID will be analysed according to the dose of S64315 planned to be administered. 
- Evaluable Set (DLTES): 
All patients from the SS who are evaluable for DLT according to the DLT assessment at the 
end of cycle 1. A patient is not considered evaluable for DLT if he/she: 
- 
Permanently discontinued treatment before C1D28 for reasons other than DLT. 
- 
Did not undergo a DLT assessment at the end of Cycle 1. 
- 
Did not receive the minimum exposure criteria i.e., minimum number of doses according 
to the dose administration schedule of both IMPs prescribed from study entry to DLTs 
assessment visit (end of Cycle 1 D28), unless treatment was stopped for a DLT (see 
Table (2.1) 1). 
- 
If a patient received more than the assigned IMP doses from study entry to DLT occurrence 
during the DLT assessment period, non-evaluability criteria will be reassessed by Sponsor 
and investigator (Table (2.1) 1). 
 
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Table (2.1) 1 - Minimum number of S64315 and azacitidine doses to meet minimum exposure until the end 
of cycle 1 
Schedule description 
Minimum of doses of 
S64315/azacitidine 
S64315 during the 2-week LID period (LID1 on D-13 and LID2 on 
D-6) 
2 out of 2 
S64315 (D2, D9, D16 and D23 in 28-day cycle) 
3 out of 4 
azacitidine (D1 to D7 in 28-day cycle) 
5 out of 7 
3. STATISTICAL METHODS 
3.1. General considerations 
Descriptive statistics depending on the nature of the criteria and the number of patients by dose 
level combinations: 
- For qualitative data, number of observed values, number and percentage of patients 
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 (SD), 
minimum (min) and maximum (max), median, first (Q1) and third (Q3) quartiles. 
For Event: 
- Number of patients (or cycles) having experienced the event (n). 
- Number of events that occurred (for AE analyses only) (NAE). 
- Number of patients (or cycles) at risk for the event (N). 
- Global incidence rate (%), 
o calculated as the ratio between the number of patients (or cycles) having 
experienced the event (n) and the number of patients (or cycles) at risk at the 
beginning of the study (N). 
Globally, mean, standard deviation and the percentage will be submitted only to the dose level 
combinations with sufficient number of patients. 
3.2. Disposition and baseline characteristics 
Description of disposition of patients (status, protocol deviations and analysis set), treatment 
duration and extent of exposure, as well as other baseline characteristics will be performed by 
dose level combination and overall. 
Calculation rules for general definitions (such as value prior to treatment, under treatment, 
analysable value, IMP infusion date,…) are provided in Appendix 4.1. 
Specific definitions on disposition of patients, baseline characteristics and patient follow-up are 
provided in Appendix 4.2. 
3.2.1. 
Disposition of patients 
Disposition of patients will be described overall for the Screened Set. Number of patients 
screened, included and not included, with relative reasons, will be presented. 
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Disposition of patients at the time of inclusion will also be described overall and by planned 
treatment dose for the IS. Number of patients included, with relative conformity to protocol, 
and withdrawn, with relative reasons, will be presented. 
Furthermore, disposition of patients for the IS will also be described after inclusion, separately 
for LID period and for each cycle. Number of patients ongoing at the given LID period or cycle, 
and withdrawn, with relative reasons, will be presented. 
3.2.2. 
Protocol deviations 
Protocol deviations before or at inclusion, as well as after inclusion, will be described in the 
IS, overall and by category of deviations (based on International Conference on 
Harmonisation (ICH) E3 guideline and ICH E3 Q&A). Number of protocol deviations 
(NPD), number and percentage of patients with at least one protocol deviation will be 
presented. 
3.2.3. 
Analysis sets and subgroups 
The number of patients in each analysis set (studied analysis set and reference analysis set), and 
reasons for exclusion will be described. 
Listings of patients with their membership, or not, of each analysis set and of excluded patients 
with reasons for exclusion will be provided. 
3.2.4. 
Demographic data and other baseline characteristics 
3.2.4.1. 
Demographic data 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for variables measured on a continuous scale, for patients of the IS: 
-
Age.
The frequency distribution (n, %) will be provided for patients of the IS by dose level 
combination and overall for variables measured on a nominal scale for the following classes: 
-
Age ([18-65[ years, [65-85[ years, ≥ 85 years).
-
Gender (Female, Male).
-
Race (Caucasian/White, Black/African American, American Indian/Alaska Native,
Asian, Native Hawaiian/Other Pacific Islander, Other).
-
Ethnicity (Hispanic or Latino, Not Hispanic or Latino).
3.2.4.2. 
Pregnancy test 
The frequency distribution (n, %) will be provided for female patients of the IS by dose level 
combination and overall for variables measured on a nominal scale for the following cases: 
-
Pregnancy test (Yes, No).
-
Positive pregnancy test (Yes, No).
-
Patient childbearing potential (Yes, No).
3.2.4.3. 
Disease history 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for variables measured on a continuous scale for: 
-
Disease duration (years).
-
Treatment-free interval since previous AML treatment line (days).
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- 
Treatment-free interval since previous (MyeloDysplastic Syndrome) MDS treatment 
line (days). 
The frequency distribution (n, %) will be provided in patients of the IS by dose level 
combination and overall for variables measured on a nominal/ordinal scale according to the 
following classes: 
- 
Disease duration (≤ 1 years, ]1-2 years], ]2-4 years] , > 4 years). 
- 
Treatment-free interval since previous AML treatment line (≤ 30 days, ]30-60 days], > 
60 days). 
- 
Treatment-free interval since previous MDS treatment line (≤ 30 days, ]30-60 days], > 
60 days). 
- 
Patient with at least one progression during or after a previous treatment line for AML 
(Yes, No). 
- 
Subtype of AML: 
• AML with recurrent genetic abnormalities. 
• AML with myelodysplasia-related changes. 
• Therapy-related myeloid neoplasms. 
• AML, not otherwise specified. 
• Myeloid sarcoma. 
• Myeloid proliferations related to Down syndrome. 
- 
Disease status (In relapse, Refractory to previous treatment, Treatment-naïve for AML). 
- 
Type of AML (De novo, Secondary). 
- 
FAB: French-American-British (FAB) classification. 
- 
Cytogenetics risk category (Favorable, Intermediate, Intermediate I, Intermediate II, 
Adverse, Not assessable). 
- 
Red blood cell transfusion dependent (Yes, No). 
- 
Platelets transfusion dependent (Yes, No). 
- 
Presence of myelodysplasia. 
- 
Gene Mutation research at diagnosis (No, Yes). 
- 
List of genes tested (No, Yes). 
- 
Presence of gene mutation (Absent, Present). 
 
A listing of key demographic and disease characteristics will also be presented. 
3.2.4.4. 
Previous therapies 
Previous therapies for AML will be summarized for patients in the IS. The following categorical 
variables will be described by frequency distribution (n, %): 
- 
Number of patients with at least one previous surgery, one previous radiotherapy, one 
previous drug treatment and one previous transplant. 
- 
Number of patients by combination of previous therapies (drug treatment + 
radiotherapy, drug treatment + transplant, drug treatment + surgery, radiotherapy + 
transplant, radiotherapy + surgery, transplant + surgery, drug treatment + radiotherapy 
+ transplant, surgery + radiotherapy + transplant, drug treatment + surgery + 
radiotherapy, drug treatment + surgery + transplant, drug treatment + surgery + 
radiotherapy + transplant). 
- 
Number of patients by type of previous transplant (autologous stem cell, allogenic stem 
cell). 
- 
Number of treatment lines by class (0, 1, 2, 3, 4-7, >7). 
- 
Number of relapses (0, 1, 2, 3, 4-7, >7). 
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- 
Number of patients who received some specific treatments lines. 
- 
Previous therapies by pharmacological class. 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for variables measured on a continuous scale including: 
- 
Number of treatments lines. 
- 
Number of relapses. 
3.2.4.5. 
Signs and symptoms related to AML 
The number and percentage of patients with signs and symptoms at baseline will also be 
summarized by System Organ Class (SOC) and Preferred Term (PT) in patients of IS. 
3.2.4.6. 
Clinical laboratory baseline evaluation 
Laboratory analysis as described in Section 3.4.4 will be analysed in patients of the IS by dose 
level combination and overall. 
For Hepatitis markers B virus surface antigen (HbsAg), B virus surface antibody 
(HbsAb), B virus core antibody (HbcAb), hepatitis C virus (HCV) RNA-PCR, hepatits E 
virus (HEV) RNA-PCR: Descriptive statistics at baseline by classes (negative, positive).  
Hepatitis B virus (HBV)-DNA tests: if HbsAg or HbcAb positive at baseline. 
 
3.2.4.7. 
Initial disease assessments 
The frequency distribution (n, %) will be provided in patients of the IS by dose level 
combination and overall. The following categorical variables will be described by frequency 
distribution (n, %): 
- 
BM blasts (%)  
- 
BM Auer rods 
- 
Presence of Myelodysplasia 
- 
Neutrophils 
- 
Platelets 
- 
PB Blasts (%) 
- 
Platelets transfusion dependent 
- 
Red blood cells transfusion dependent 
3.2.4.8. 
Medical and surgical history not related to AML 
Medical and surgical history other than for the AML will be summarized by SOC and PT 
according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary in patients 
of the IS. 
3.2.4.9. 
Vital signs and clinical examination at baseline 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for variables measured on a continuous scale including: 
- 
Weight (kg). 
- 
Height (cm). 
- 
Supine systolic blood pressure (SBP). 
- 
Supine diastolic blood pressure (DBP). 
- 
Supine heart rate (HR). 
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The frequency distribution (n, %) will be provided in patients of the IS by dose level 
combination and overall for variables measured on a nominal scale according to the following 
classes: 
- 
ECOG (0, 1, 2, 3, 4). 
- 
Supine SBP (< 90 mmHg , [90-140 mmHg[ , ≥ 140 mmHg). 
- 
Supine DBP(< 60 mmHg , [60-90 mmHg[ , ≥ 90 mmHg). 
- 
Supine HR (< 60 bpm , [60-100 bpm[ , ≥ 100 bpm). 
3.2.4.10. Centralised ECG at baseline 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for variables measured on a continuous scale including QT interval (uncorrected) and 
Fridericia QT interval corrected for heart rate (QTcF). 
The frequency distribution (n, %) will be provided in patients of the IS by dose level 
combination and overall for variables measured on a nominal scale according to the following 
classes: 
- 
Presence of ECG abnormalities (Yes, No). 
- 
Presence of clinically significant ECG abnormalities (Yes, No). 
- 
QT interval (uncorrected and Fridericia corrected) in classes (≤ 450 ms, ]450-480] ms, 
]480-500] ms and > 500 ms).  
3.2.4.11. LVEF at baseline 
Descriptive summary statistics (n, mean, SD, median, min, max, median, Q1, Q3) will be 
provided for LVEF. The frequency distribution (n, %) will also be provided in patients of the 
IS by dose level combination and overall, according to the following classes: 
- 
LVEF (< 50%, [50-70%], >70%). 
3.2.4.12. Chest X-Ray 
The frequency distribution (n, %) will be provided in patients of the IS by dose level 
combination and overall for Chest X-Ray, according to the following classes: 
- 
Chest X-Ray performed (Yes, No). 
3.2.4.13. TLS prevention 
All concomitant treatments for TLS prevention taken at inclusion and before the treatment 
period will be described for each dose level combination and overall in the SS, by Anatomical 
Therapeutic Chemical (ATC) code into 4 levels (Pharmacological class, Pharmacological sub-
class, therapeutic class, Preferred name). TLS risk category, type of hydration performed and 
anti-hyperuricaemic administration will also be presented. 
3.2.5. 
Treatments of patients 
3.2.5.1. 
Extent of treatment exposure and treatment compliance 
Details concerning definition on extent of exposure, treatment compliance are provided in 
Appendix 4.2.1.5. 
For S64315 and azacitidine separately the frequency distribution (n, %) or descriptive summary 
statistics (n, mean, SD, median, min, max, median, Q1, Q3) as applicable will be provided in 
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patients of the SS by planned dose level combination and overall for variables measured on a 
nominal scale according to the following classes: 
• Extent of exposure*: 
- 
The global treatment duration (combined measure for S64315/azacitidine): 
summary statistics. 
- 
Treatment duration (weeks) overall and by treatment period (LID/Combination 
treatment). 
- 
Treatment duration (weeks) during combination treatment period (i.e., excluding 
LID) (< 4 weeks, [4-12[ weeks, [12-24[ weeks, [24-36[ weeks, [36-48] weeks, >48 
weeks). 
- 
LID duration (]0-1] week, ]1-2] weeks and > 2 weeks). 
- 
Number of cycles (1 cycle, 2 cycles, 3-6 cycles, 7-10 cycles, > 10 cycles) during the 
combined treatment period. 
- 
Number of patients by cycle (LID, Cycle 1, Cycle 2, etc). 
• Treatment compliance*: 
- 
Cumulative dose (mg) for S64315/ Cumulative dose (mg/m2) for azacitidine overall, 
by cycle (including LID), and for combination treatment. 
- 
Dose intensity (DI) (mg/week) for S64315/ DI (mg/m2/day) for azacitidine overall, 
by cycle (including LID), and for combination treatment. 
- 
Relative Dose Intensity (RDI) (%) for S64315/azacitidine overall, by cycle 
(including LID), and for combination treatment. 
- 
RDI for S64315(< 35%, [35-65[%, [65-100[%, ≥ 100%) overall, by cycle, and per 
treatment period (LID/Combination treatment). 
- 
RDI for azacitidine (< 62%, [62-85[%, [85-100[%, ≥ 100%) overall, by cycle, and 
per treatment period (Combination treatment).  
- 
Treatment interruption (Yes/No) during treatment period (including LID). 
- 
Reason of treatment interruption (Medical reason, Non-medical reason, Missing). 
- 
LIDLIDNumber of cycles with at least one treatment interruption for S64315 during 
treatment period (including LID).  
- 
Number of cycles with at least one treatment interruption for azacitidine during 
treatment period.  
- 
Cycle delayed (Yes/No) during treatment period (including LID). 
- 
Reason for cycle delayed (Medical reason, Non-medical reason, Missing). 
- 
Number of cycles delayed during treatment period (including LID). 
- 
Number of cycles delayed (1, 2, > 2) during treatment period (including LID). 
• Specifically for S64315, the summary of treatment compliance will also will include: 
- 
Dose modified (Yes/No) during treatment period (including LID). 
- 
Number of dose modifications during treatment period (including LID). 
- 
Number of dose modifications (1, 2, > 2) during treatment period (including LID). 
- 
Time to first dose modification (days) during treatment period (including LID). 
- 
Partial dose administered (Yes/No) during treatment period (including LID). 
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- 
Number of cycles with partial dose for S64315 during treatment period (including 
LID).  
- 
Number of cycles with partial dose for S64315 (1, 2, > 2) during treatment period 
(including LID).  
• Specifically for azacitidine, the summary of extent of exposure will include: 
- 
Average number of days dosed per cycle with planned dose level for azacitidine 
overall. 
- 
Average number of days dosed overall.  
- 
Number of azacitidine interruption days. 
* Applicable for both S64315 and azacitidine if not specified. 
3.2.5.2. 
Concomitant treatments 
Details concerning definition on concomitant treatments are provided in Appendix 4.2.1.6. 
All concomitant treatments taken during the study period will be described for each 
administered dose level combination, and overall, in the SS, by ATC code into 4 levels 
(pharmacological class, pharmacological sub-class, therapeutic class and preferred name) and 
into 1 level (pharmacological class only). Concomitant treatments only during the study 
period are described because we will have an abbreviated CSR for the CL1-64315-004. 
3.2.6. 
Other observations related to patient follow-up 
We will have an abbreviated CSR for the CL1-64315-004, therefore, follow-up analysis is not 
applicable. 
3.3. Efficacy analysis 
We will have an abbreviated CSR for the CL1-64315-004, therefore, efficacy analysis is not 
applicable. 
3.4. Safety endpoints 
All safety analyses will be performed in the SS (resp. DLTES for DLT analysis) by treatment 
dose level combination and overall. The treatment period is defined from first IMP intake up to 
last IMP intake date + (*) days. 
(*) 30 days for AE and death analysis, 28 days for clinical laboratory evaluation, vital signs and 
clinical examination, centralized ECG and LVEF analysis.  
Qualitative data will be presented in number and percentage of patients per class, while 
quantitative data will be presented in mean, SD, min and max, median, Q1 and Q3. 
Calculation rules for expressions of safety endpoints, as well as general definitions (such as 
value prior to treatment / under treatment, analysable value, first and last IMP intake dates…), 
are provided in Appendix 4.1. 
Calculation rules for safety endpoints and other specific definitions are provided in Appendix 
4.2. 
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3.4.1. 
Dose limiting toxicity 
Number and percentage of patients with at least one DLT before the end of the first cycle, type 
of DLT and listing of PTs, verbatim and worst grade of AE declared as DLT will be provided 
in the DLTES. 
Listing of patients with at least one DLT, type of DLT and PTs, verbatim will also be provided 
in the DLTES. 
3.4.2. 
Adverse events 
Number of events, number and percentage of patients reporting at least one event, presented by 
primary SOC and PT (depending on the analysis), will be provided for SAEs over the study 
period and for treatment emergent adverse events (TEAEs). 
TEAE will be described according to the seriousness, the worst grade, the severity, the 
relationship, the action taken regarding the IMP(s), the requirement of added therapy and the 
outcome. 
Of note, the seriousness and the relationship with the IMPs (S64315 and/or azacitidine) of the 
adverse event are based on the investigator’s opinion, but it includes also the sponsor decision 
to upgrade the seriousness and/or the relation to IMP(s) (the causal relationship will not be 
upgraded for EudraCT analyses). 
The National Cancer Institute Common Terminology Criteria for Adverse Events Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) classification version 5.0 will be used 
to classify all adverse events. 
3.4.3. 
Death 
Number and percentage of deaths will be described on each period (during the treatment and 
follow-up period / during the treatment period / during the follow-up period). Reason of death 
on each period will be provided in terms of qualitative data. During treatment period, reason 
will be presented by SOC and PT, whereas during the follow-up period it will be presented in 
terms of either progressive disease or other reason. 
3.4.4. 
Clinical laboratory evaluation 
Descriptive statistics on quantitative value and value by grade at baseline and worst grade on 
treatment according to the grade at baseline will be provided for gradable parameters (see 
Table (3.4.4) 1). 
 
 
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Table (3.4.4) 1 – Gradable parameters 
Parameter 
Worst Highest 
Worst lowest Gradable at 
baseline* 
Blood 
biochemistry 
Alanine 
aminotransferase 
(ALT) 
High ALT 
NA   
No 
Albumin 
NA  
Low albumin 
Yes 
Alkaline 
phosphatase 
(ALP) 
High ALP 
NA   
No 
Amylase 
High amylase 
NA 
Yes 
Aspartate 
aminotransferase 
(AST) 
High AST 
NA   
No 
Bilirubin (total) 
High total 
bilirubin  
NA   
No 
Cholesterol (total) High cholesterol NA   
Yes 
Creatine 
phosphokinase 
(CPK) 
High CPK 
NA   
Yes 
Gamma-glutamyl 
transferase 
(gamma-glutamyl 
transpeptidase) 
(GGT) 
High GGT 
NA   
No 
Creatinine 
(serum) 
High serum 
creatinine 
NA  
 Yes 
Glucose 
NA 
Hypoglycemi
a 
Yes 
Lypase 
High lipase 
NA 
Yes 
Magnesium 
Hypermagnesem
ia 
Hypomagnes
emia 
Yes 
Potassium 
Hyperkalemia 
Hypokalemia 
Yes 
Sodium 
Hypernatremia 
Hyponatremi
a 
Yes 
Triglycerides 
High 
triglycerides 
NA  
Yes 
Ionized calcium 
High ionized 
calcium 
Low ionized 
calcium 
Yes 
Blood 
haematology 
Haemoglobin 
High 
haemoglobin 
Anemia 
Yes for Low /  
No for High 
Lymphocytes 
NA 
Low 
lymphocytes 
Yes 
Neutrophils 
NA   
Low 
neutrophils 
Yes 
 
White blood cells 
(WBC) 
NA 
Low WBC 
Yes 
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Platelets 
NA   
Low 
platelets   
Yes 
Blood 
coagulation 
Activated partial 
thromboplastin 
time (aPTT) 
High aPTT 
NA   
Yes 
 
Descriptive statistics on quantitative value and value by reference ranges at baseline and worst 
value on treatment according to baseline, with respect to the lower-limit notmal (LLN) and the 
upper-limit normal (ULN) or by classes (<LLN / [LLN-ULN] / >ULN or normal / mild / 
moderate / severe for creatinine clearance) will be provided for non-gradable parameters (see 
Table (3.4.4) 2) and for parameters gradable post-baseline but non-gradable at baseline, in 
which case only baseline values will be presented. 
 
Table (3.4.4) 2 – Non Gradable parameters 
Parameter 
Worst Highest 
Worst lowest 
Blood 
biochemistry 
Bicarbonates 
NA 
Low bicarbonates 
Uric acid 
High uric acid 
NA 
Calcium (total) 
Hypercalcemia 
Hypocalcemia 
Creatinine 
clearance 
(approximated 
by 
the 
Modification of Diet in Renal 
Disease Glomerular Filtration 
Rate (MDRD_GFR)) 
NA 
Low creatinine 
clearance 
(Normal/mild/ 
moderate/severe) 
Direct bilirubin 
High direct 
bilirubin 
NA   
High-density lipoprotein (HDL) High HDL 
NA   
Lactate dehydrogenase (LDH) 
High LDH 
NA   
Low-density lipoprotein (LDL) 
High LDL 
NA   
Phosphorus 
NA 
Hypophosphatemi
a 
Troponin I 
High troponin I 
NA   
Troponin T 
High troponin T 
NA   
 
 
 
Urea 
High urea 
NA   
Urea nitrogen (blood) (BUN) 
High BUN  
NA   
Blood 
haematology 
Basophils 
NA   
Low basophils 
Eosinophils 
High eosinophils 
NA   
Haematocrit 
High haematocrit 
Low haematocrit  
Monocytes 
High monocytes 
NA   
Red Blood Cell (RBC) Count 
High RBC 
Low RBC 
Lymphocytes 
High lymphocytes 
NA 
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White Blood Cell (WBC) Count High WBC 
NA 
Thyroid 
function 
T3 free 
High T3 free 
Low T3 free 
T4 free 
High T4 free 
LowT4 free 
Thyroid Stimulating Hormone 
(TSH) 
High TSH 
Low TSH 
Cardiac 
markers 
Creatine 
PhosphoKinase 
Myocardial Band (CPK-MB) 
activity 
High CPK-MB 
activity 
NA   
CPK-MB mass 
High CPK-MB 
mass 
NA   
Brain Natriuretic Peptide (BNP) High BNP 
NA   
Blood 
coagulation 
International normalized ratio 
(INR) 
High INR 
NA 
 
For urinalysis parameters haematuria, glycosuria, proteinuria, ketonuria: Descriptive 
statistics at baseline and worst value on treatment period, by classes (negative, trace, positive). 
 
3.4.5. 
Vital signs and clinical examination 
Vital signs and clinical examination will be described, in terms of quantitative value and value 
by classes at baseline, worst (highest and/or lowest) value under treatment, and absolute and 
change (and relative change for weight as well) from baseline to worst (highest and/or lowest) 
value under treatment for: 
- 
SBP (<90, [90-140[ and ≥ 140 mmHg). 
- 
DBP (<60, [60-90[, ≥ 90 mmHg). 
- 
HR (<60, [60-100[ and ≥ 100 bpm). 
- 
ECOG status (0, 1, 2, 3, 4, 5). 
- 
Weight (relative baseline change measured as <-10%, ≥ -10%). 
3.4.6. 
Centralised ECG 
QT interval (uncorrected and corrected Fridericia) during the treatment period will be described 
in terms of: 
- 
Maximum absolute prolongation. 
- 
Maximum change from baseline. 
Values and changes from baseline of corrected QT interval will be described in classes, 
considering thresholds defined in ICH E14: 
- 
Values: ≤ 450, ]450-480], ]480-500] and > 500. 
- 
Changes: ≤ 30, ]30-60] and > 60. 
Emergent ECG and emergent clinically significant ECG abnormality during treatment period 
will be described. 
3.4.7. 
LVEF 
LVEF will be described, in terms of quantitative value: 
- 
At baseline. 
- 
Worst (lowest) post-baseline value under treatment. 
- 
Change from baseline to worst (lowest) post-baseline value under treatment. 
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Moreover, values and change from baseline of LVEF will be described in classes: 
- 
Values:<40 / [40-50[ / ≥ 50%. 
- 
Change and relative change: ≤ -10% / > -10%. 
The worst (lowest) value under treatment will also be described by grade according to NCI-
CTCAE version 5.0 (Grade 0 / Grade 2/ Grade 3 / Grade 4). 
3.5. Exploratory analysis 
All exploratory biomarker analysis results will be presented in a separate report. 
3.6. Interim analysis 
N.A. 
 
4. APPENDICES 
4.1. General analytic definitions 
Definitions below correspond to calculation rules for expressions defined in Section 3.2, 3.3, 
3.4 as well as definition of value prior to treatment / under treatment, analysable value, first and 
last IMP intake dates and other general definitions. 
4.1.1. 
Expressions 
Reliable value 
For biological and coagulation samplings: 
Identified with flag BIOFG (“Non analysable value”) different from 1 and non-missing 
result. 
For other panels: 
Non-missing result. 
Value at baseline is defined as the last reliable (i.e. last non-missing) value prior to treatment. 
Note: In case of patient included but not treated (i.e. patients with treatment duration equal to 
0): value at baseline is defined as the last analysable value prior to the LID (i.e. "Visit<C000"). 
Baseline value of cycle n is defined as the last reliable (i.e. last non-missing) value prior to first 
study treatment intake of cycle n. 
Value at the Cycle n Day n is defined as the first reliable (i.e. first non-missing) value at the 
visit. 
Post-baseline value is defined as available value after the first IMP intake or, in case of missing 
first intake, after the date visit superior (>) to last inclusion visit (A000). 
End post-baseline value is defined as the last reliable post-baseline value of the criteria of 
interest during the treatment period. 
Worst post-baseline value is defined as the worst reliable post-baseline value of the criteria of 
interest during the treatment period. 
Lowest/highest post-baseline value is defined as the lowest/highest value during the treatment 
period. 
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4.2. Specific analytic definitions and data handling conventions 
4.2.1. 
Study patients: Disposition, baseline characteristics and follow-up 
4.2.1.1. 
Disposition of patients 
All withdrawal reasons occurred in the study will be taken into account. 
4.2.1.2. 
Protocol deviations 
For the description of protocol deviations, the 6 following categories are considered 
in accordance with ICH E3 guideline and ICH E3 Q&A: 
- Selection/inclusion criteria not fulfilled. 
- Patient having withdrawal criteria but not withdrawn. 
- Incorrect treatment or dose received. 
- Forbidden concomitant treatment. 
- Endpoint assessment possibly affected. 
- Safety possibly affected. 
4.2.1.3. 
Demographic data and other baseline characteristics 
4.2.1.3.1. 
Demographic data 
Age (years) is calculated in the ClinTrial database as: 
(Date of inclusion – Date of birth )/365.25. 
The result is truncated and not rounded. If the day and/or month of inclusion date and/or birth 
date is/are missing, the calculation is done by using the year. 
4.2.1.3.2. 
History of AML 
Disease duration 
Disease duration (years) is calculated as: 
(Inclusion visit date – Date of the first diagnosis)/365.25. 
Treatment free interval 
Treatment-free interval since previous AML treatment line (days) and Treatment-free interval 
since previous MDS treatment line (days) are defined as: 
(Date of first IMP intake – Date of end of the last prior drug therapy). 
Of note, in case of partial or incomplete dates: 
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The existence of a previous transplant (Yes/No) is defined from the presence, or not of 
previous transplant date at inclusion date. 
The existence of a previous surgery (Yes/No) is defined from the presence or not of a verbatim 
for the previous surgery at inclusion visit. 
The number of treatment lines is calculated as the sum of all previous treatment lines 
received, since diagnosis date of the studied disease (regardless the type of therapy). 
The number of relapses is calculated as the sum of all previous lines with CR (including CR 
MRD-, CR, CRi and Haematologic relapse responses) as best response received, since 
diagnosis date of the studied disease (regardless the type of therapy). 
The specific treatment lines described with the corresponding code lists are the following: 
- 3427.1 Cytarabine 20221(WHODDB3). 
- 3601.2 Treatments containing fludarabine 20221 (WHODDB3). 
- 3428.2 Anthracyclines and related substances 20221(WHODDB3). 
- 4273.0 Hypomethylating agents (HMAs) for CL164315004 study 20221 (WHODDB3). 
- 3430.1 Azacitidine 20221(WHODDB3). 
- 3422.1 Decitabine 20221(WHODDB3). 
- 3429.1 Lenalidomide 20221(WHODDB3). 
- 3594.2 Investigational drugs 20221(WHODDB3). 
- Stem cell transplant and bone marrow transplant (no code list associated – To refer to 
previous transplant section allograft or autograft) 
- 1869.0 Systemic and local treatment containing glucocorticoids DDB320221. 
- 1728.2 Treatments containing an alkylating agent DDB320221. 
- 3600.2 Treatments containing cyclophosphamide 20221(WHODDB3). 
- 3602.0 Treatments containing antimetabolites agents DDB320221. 
- 3609.0 Treatments containing protein and tyrosine kinase inhibitors DDB320221. 
- 3605.1 Treatments containing etoposide 20221(WHODDB3). 
- 3914.0 Granulocyte colony stimulating factor 20221(WHODDB3). 
- 4131.1 Treatments containing enasidenib 20221(WHODDB3). 
- Gemtuzumab 
ozogamicin 
(Mylotarg®) 
(drug 
code: 
15959801001, 
version 
WHODDB32022.1) 
- Ivosidenib (Tibsovo®) (drug code : 09165501001, version WHODDB32022.1) 
No substitution of missing or incomplete previous drug treatments are applied. 
4.2.1.3.6. 
Initial disease assessment 
PB blasts in blood expressed in SI unit (G/L) in “blood haematology” form will be converted 
to % unit by dividing by the corresponding WBC value. 
Information concerning platelets transfusion-independence prior to LID1 and red blood cells 
transfusion-independence prior to LID1 (i.e. before the first IMP intake) will be retrieved from 
the “History of the Acute Myeloid Leukaemia” e-CRF form. The patients having received a 
transfusion prior to LiD1 will be considered as transfusion-dependent. 
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4.2.1.4. 
TLS prevention 
TLS prevention treatment lines (anti-hyperuricemic therapy) are referenced in the code list 
n°3399.0 WHOODB3 20221. 
4.2.1.5. 
Extent of exposure and treatment compliance 
Global treatment duration 
Global treatment duration (weeks) is defined as (min [max (last intake date of the last cycle 
azacitidine + 21 days, last intake date of S64315 + 6 days), death date, withdrawal date] - first 
IMP intake + 1)/7. 
Treatment duration for S64315 including LID period (QW) 
Treatment duration (days) for S64315 is defined as [(min (last infusion date + 6 days, death 
date, withdrawal date) - first S64315 infusion date) +1]. 
Treatment duration (weeks) for S64315 is defined as [(min (last infusion date + 6 days, death 
date, withdrawal date) - first S64315 infusion date) +1] /7. 
Treatment duration for S64315 excluding LID period (QW) 
Treatment duration (days) for S64315 is defined as [(min (last infusion date + 6 days, death 
date, withdrawal date) - first S64315 infusion date of cycle 1) +1]. 
Treatment duration (weeks) for S64315 is defined as [(min (last infusion date + 6 days, death 
date, withdrawal date) - first S64315 infusion date of cycle 1) +1] /7. 
Treatment duration for azacitidine  
Treatment duration (days) for azacitidine is defined as [min (last intake date of the last cycle + 
21 days,  death date, withdrawal date) - first azacitidine intake + 1]. 
Treatment duration (weeks) for azacitidine is defined as [min (last intake date of the last cycle 
+ 21 days,  death date, withdrawal date) - first azacitidine intake + 1]/7. 
S64315 treatment duration in LID period: 
S64315 treatment duration in LID period LID(days) is defined as [min (first S64315 infusion 
date of cycle 1-1, death date, withdrawal date) – first S64315 infusion date of LID1]+1. 
Note: In case of missing first S64315 at cycle 1, S64315 treatment duration in LID period is 
defined as [min(last S64315 infusion date in LID +6, death date, withdrawal date) -  first S64315 
infusion date of LID]+1. LIDLID 
LID period duration (weeks): LID period duration (days) / 7. 
Cycle duration for S64315 
Duration of cycle i (weeks) for S64315 is defined as [first IMP intake of cycle (i+1) – first IMP 
intake of cycle i] /7. 
Note: The duration of the last cycle for S64315 will be estimated to be 4 weeks for the 
calculation of dose intensity and relative dose intensity at the last cycle. 
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The dose intensity (mg/ week) for S64315 per cycle is defined as the cumulative dose (mg) 
received during the cycle divided by the cycle duration in weeks. 
𝐷𝐼 (𝑚𝑔
𝑤𝑘) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑤𝑒𝑒𝑘𝑠)
. 
The duration of the last cycle will be estimated to be (*) weeks. 
(*): 4 weeks for regimen QW, 2 week for LID. 
Relative dose intensity (RDI) for S64315 
The RDI (%) for S64315 per patient measures the percentage of the total trial dose planned that 
was really administered. It is defined as the ratio of the dose intensity (mg/week) to the initial 
planned dose intensity (mg/week)  
𝑅𝐷𝐼 (%) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐷𝐼 (𝑚𝑔/𝑤𝑘)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 (𝑚𝑔/𝑤𝑘) ∗100. 
The RDI (%) for S64315 per cycle is defined as the ratio of the dose intensity (mg/week) at 
cycle i (including LID cycles) to the planned dose intensity (mg/week). 
𝑅𝐷𝐼 (%) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 
𝐷𝐼 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑚𝑔/𝑤𝑘)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑚𝑔/𝑤𝑘) ∗100. 
Treatment interrupted for S64315 
A treatment interruption is defined according to the S64315 infusion e-CRF page (Did the 
patient receive the IMP infusion (Yes/No)). 
Number of cycles with at least one treatment interruption for S64315 experienced by a 
patient over the treatment period will be calculated.  
Cycle delay for S64315 
A cycle delay is defined according to the S64315 infusion e-CRF page (infusion postponed 
(Yes/No) at D2 of the cycle i or of LID2). Moreover, a delay of LID2 will be also considered 
if the duration of the LID1 is higher than 7 days, while a delay of cycle i will be also considered 
if the duration of the cycle i-1 is higher than (*). In case of missing cycle delay reason, reason 
of cycle delay will be considered as unknown. The delay in days will be derived, based on the 
dates of administration. 
Delay (days) of cycle i = (first IMP intake of cycle i) – (first IMP intake of cycle i-1 + x days). 
(*): 30 days for regimen QW (theoretical cycle duration + 2 days for potential technical or 
logistical difficulty). In the delay duration formulae above x=30. 
(*) x=16 days if Cycle i-1 is the LID period.  
Number of cycles delayed for S64315 experienced by a patient over the treatment period will 
be calculated among patients experiencing a cycle delay. 
Dose modification for S64315 
A dose modification is defined according to the S64315 infusion e-CRF page (Has the dose 
been modified since the last infusion (Yes/No), with a dose level different from the dose level 
at previous infusion). 
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Number of dose modifications for S64315 experienced by a patient over the treatment period 
will be calculated among patients experiencing a dose modification. 
Time to first dose modification for S64315 will be calculated among patients experiencing a 
dose modification from the first study drug intake until the first dose modification. 
Partial dose administered for S64315 
A partial dose administered is defined according to the S64315 infusion e-CRF page (Was full 
dose administered ? (Yes/No)) 
Number of cycles with partial dose experienced by a patient over the treatment period will be 
calculated among patients. 
Number of days dosed for azacitidine  
The number of days dosed for azacitidine is defined as the total number of days with azacitidine 
intake (overall and by cycle).  
Average number of days dosed per cycle for azacitidine  
The average number of days dosed per cycle for azacitidine is defined as the total number of 
days dosed for azacitidine divided by the number of cycles according to the period of interest 
(i.e. for overall period: number total of cycles / for each cycle: 1): 
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑑𝑎𝑦𝑠 𝑑𝑜𝑠𝑒𝑑 𝑝𝑒𝑟 𝑐𝑦𝑐𝑙𝑒  = 𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑑𝑜𝑠𝑒𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒𝑠
. 
Number of days dosed with planned dose level for azacitidine 
The number of days dosed with planned dose level for azacitidine is defined as the total number 
of days with azacitidine intake corresponding to the planned dose level of 75 mg/m2 (the actual 
dose administered is equal to 75mg/m2 or within the interval 75 ±7.5 mg/m2). 
Average number of days dosed per cycle with planned dose level for azacitidine  
The average number of days dosed with planned dose level for azacitidine per cycle is defined 
as the total number of days dosed with planned dose level for azacitidine divided by the number 
of cycles according to the period of interest (i.e. for overall period: number total of cycles / for 
each cycle: 1): 
𝐴𝑣𝑒𝑟𝑎𝑔𝑒 𝑑𝑎𝑦𝑠 𝑑𝑜𝑠𝑒𝑑 𝑤𝑖𝑡ℎ 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑙𝑒𝑣𝑒𝑙 𝑝𝑒𝑟 𝑐𝑦𝑐𝑙𝑒
= 𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑑𝑜𝑠𝑒𝑑 𝑤𝑖𝑡ℎ 𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑙𝑒𝑣𝑒𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑦𝑐𝑙𝑒𝑠
. 
 
Real administrated dose of azacitidine will be recorded directly from azacitidine injection e-
CRF page (Administered dose (mg)). 
Planned dose intensity (PDI) for azacitidine:  
Planned dose intensity (day): 75 mg/m2/day (fixed). 
Planned dose intensity (cycle or overall): (75 mg/m2/day (fixed) * 7) / 28. 
 
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Cumulative dose for azacitidine 
The cumulative dose (mg/m²) for azacitidine per patient during a time period (during the 
treatment period or per cycle) is the sum of the total dose levels that the patient received between 
the first and last treatment intake according to the compliance. 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) = 
∑
(𝑅𝑒𝑎𝑙 𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑒𝑑 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐵𝑆𝐴 (𝑚2)
)
𝑡𝑖𝑚𝑒𝑝𝑒𝑟𝑖𝑜𝑑
. 
Dose intensity (DI) for azacitidine 
The dose intensity (mg/m²/day) for azacitidine per patient is defined as the cumulative dose 
(mg/m²) received during the treatment period divided by the overall treatment duration of 
azacitidine. 
𝐷𝐼 (𝑚𝑔/𝑚²
𝑑𝑎𝑦) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²)
𝑂𝑣𝑒𝑟𝑎𝑙𝑙 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑎𝑧𝑎𝑐𝑖𝑡𝑖𝑑𝑖𝑛𝑒 . 
The dose intensity (mg/ day) for azacitidine per cycle is defined as the cumulative dose (mg) 
received during the cycle divided by the cycle duration of azacitidine. 
𝐷𝐼 (𝑚𝑔/𝑚²
𝑑𝑎𝑦) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑑𝑜𝑠𝑒 (𝑚𝑔/𝑚²) 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝐶𝑦𝑐𝑙𝑒 𝑖 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑎𝑧𝑎𝑐𝑖𝑡𝑖𝑑𝑖𝑛𝑒 
. 
Relative dose intensity (RDI) for azacitidine 
The relative dose intensity (%) for azacitidine per patient measures the percentage of the total 
trial dose planned that was really administered. It is defined as the ratio of the dose intensity 
(mg/m²/day) to the initial planned dose intensity (mg/m²/day). 
𝑅𝐷𝐼 (%) 𝑝𝑒𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 = 
𝐷𝐼 (𝑚𝑔/𝑚²/𝑑𝑎𝑦)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 (𝑚𝑔/𝑚²/𝑑𝑎𝑦) ∗100. 
The relative dose intensity (%) for azacitidine per cycle is defined as the ratio of the dose 
intensity (mg/m²/day) at cycle i to the planned dose intensity (mg/m²/day). 
𝑅𝐷𝐼 (%) 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 = 
𝐷𝐼 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑚𝑔/𝑚²/𝑑𝑎𝑦)
𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝑑𝑜𝑠𝑒 𝑖𝑛𝑡𝑒𝑛𝑠𝑖𝑡𝑦 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 (𝑚𝑔/𝑚²/𝑑𝑎𝑦) ∗100. 
Treatment interruption for azacitidine 
A treatment interruption is defined according to the azacitidine injection e-CRF page (Did the 
patient receive at least one azacitidine injection (Yes/No)). 
Number of cycles with at least one treatment interruption for azacitidine experienced by a 
patient over the treatment period will be calculated.  
Number of azacitidine interruption days experienced by a patient over the treatment period 
will be calculated among patients experiencing a treatment interruption. 
The number of azacitidine interruption days is the number of days on which azacitidine was 
scheduled to be administered but was not actually administered.  
Cycle delay for azacitidine 
A cycle delay is defined according to the azacitidine injection e-CRF page (Was the injection 
day postponed (Yes/No) at D1 of the cycle). Moreover, a cycle delay of cycle i will be also 
considered if the duration of the cycle i-1 is higher than (*). In case of missing cycle delay 
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reason, reason of cycle delay will be considered as unknown. The delay in days will be derived, 
based on the dates of administration. 
For i>1, Delay (days) of cycle i = (first IMP intake of cycle i) – (first IMP intake of cycle i-1 + 
x days) 
(*):  30 days for regular cycle (theoretical cycle duration + 2 days for potential technical or 
logistical difficulty). In the delay duration formulae above x=30. 
Number of cycles delayed for azacitidine experienced by a patient over the treatment period 
will be calculated among patients experiencing a cycle delay. 
4.2.1.6. 
Concomitant treatments 
The anatomical therapeutic chemical classification (ATC code = 5 digits) is composed of 4 
levels: 
- The first (1 digit) represents the anatomo-physiological class. 
- The second (2 digits) represents the pharmacological class. 
- The third (1 digit) represents the pharmacological sub-class. 
- The last (1 digit) represents the therapeutic class. 
The existence of a concomitant treatment (Yes/No) is defined from the presence, or not, of 
an ATC classification and/or preferred name. 
The periods considered for the analysis are: 
During the study period, for which the concomitant treatment: 
- 
LIDstart date ≥ LIDinclusion date 
- 
start date < inclusion date LIDand stop date ≥ LIDinclusion date or missing 
At inclusion and before the treatment period, for which the concomitant treatment for tumour 
lysis syndrome prevention: 
- 
start date < first S64315 infusion date (during the LID period) , or 
- 
start date <= inclusion date and stop date >= inclusion date or is missing 
 
The following rules for substitution of missing or incomplete start and stop dates are so that 
the concomitance period is maximised: 
 
 
 
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The following rules for substitution of totally or partially missing start and stop dates are used 
for concomitant treatments (only further anti-leukemic therapy): 
 
 
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4.2.1.7. 
Other observations related to patient follow-up 
N.A. 
4.2.2. 
Efficacy 
N.A. 
4.2.3. 
Safety 
4.2.3.1. 
Dose Limiting Toxicity (DLT) 
A DLT is defined as: 
• A clinically significant adverse event graded according to the NCI-CTCAE version 5.0, 
observed following the administration of the test drugs. 
• Assessed as unrelated to disease progression, intercurrent illness, or concomitant 
Medications. 
• At least possibly related to the test drug(s) by the investigator and meeting any of the 
criteria included in Table (4.2.3.1) 1. 
DLT will be reported based on investigator, using the ‘Dose limiting toxicity (DLT)’ / ‘Adverse 
event’ e-CRF page, and not recalculated. 
 
Table (4.2.3.1) 1 –Toxicity criteria 
 
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4.2.3.2. 
Adverse events 
Each medical concept of adverse events coded according to the internal "multiple medical 
concept" process is taken into account as a single adverse event in the statistical analysis. 
The modalities of the adverse event (onset and end dates, severity, seriousness, action taken, 
additional therapy, relationship, outcome...) replicated by default to each medical concept are 
also taken into account in the statistical analyses. 
Emergent adverse events on treatment are defined as all adverse events: 
- which occur between the first IMP intake date (included) and the last IMP intake date "+ (*) 
days", 
or 
- which was present before the first IMP intake date and which worsen (in terms of severity) 
or become serious according to the investigator opinion between the first IMP intake date 
(included) and the last IMP intake date "+ (*) days". 
(*): 30 days for regimen QW. 
Note: Adverse events occurring or worsening or becoming serious on the day of the first IMP 
intake (if any) is considered as emergent. 
Serious adverse events are defined as all adverse events upgraded by the sponsor during the 
independent medical exam (IME) or PharmacoVigilance (PV) process (upgrade of seriousness) 
or considered as "serious" from investigator assessment. 
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Serious adverse events from investigator assessment are defined as all adverse events fulfilling 
at least one of the following seriousness criteria for immediate notification: death, 
hospitalisation, or prolongation of hospitalisation, medically important, life-threatening, 
disability/incapacity or congenital anomaly. 
A fatal adverse event corresponds to an adverse event with “Fatal” as outcome. 
Adverse events related to S64315 correspond to adverse events with relationship forced by 
the sponsor during the PV process (upgrade of relationship for adverse events assessed as 
serious according to investigator or sponsor opinion) or considered as "related" from 
investigator assessment. In other cases, the adverse events are considered as "not related to 
S64315". 
Adverse events related to azacitidine correspond to adverse events with relationship 
considered as "related" from investigator assessment. In other cases, the adverse events are 
considered as "not related to azacitidine". 
Adverse events related to S64315 and azacitidine from investigator assessment correspond 
to adverse events associated with the answer "Related" to the "Is this event related to S64315" 
question and “Related” to the “Is this event related to azacitidine” question. 
The following information will be taken into account: 
- For the analyses where the severity of the adverse event is considered, the worst severity 
from the day of emergence and during the studied period (i.e. between the first IMP intake 
date (included) and the last IMP intake date "(*) days" (included)) will be taken into account. 
- The number of patients by worst grade: for each patient, SOC and PT, we analyse the worst 
grade of events. 
- The number of events by worst grade: for each patient, SOC and PT, we analyse the worst 
grade of each event. The percentage will be calculated as the number of events of the PT 
concerned at grade X divided by the total number of events of the PT concerned. 
- For the analyses where the action taken regarding the IMP (S64315 and/or azacitidine) and 
the additional therapy requirement are considered, all the actions taken, and additional 
therapy requirements recorded from the day of emergence and on the studied period will be 
taken into account. 
However, in case of an episode of an emergent adverse event leading to studied treatment 
withdrawal reported after the last IMP intake date "+ (*) days", the adverse event will be 
considered as leading to studied treatment withdrawal during the studied period. 
- Seriousness is judged by event: if one episode is serious (whatever the time it occurs), the 
whole event will be considered as serious. 
- A severe adverse event corresponds to an adverse event with NCI-CTCAE version 5.0 grade 
3, 4 or 5. 
- Any grade corresponds to an adverse event with NCI-CTCAE version 5.0 grade 1, 2, 3, 4 or 
5. 
- All multicoded events will be taken into account in the analyses. 
- For the analysis of recovered emergent adverse event during / after treatment period, a TEAE 
is considered as recovered “during treatment period” (“after end of treatment period”, 
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For the parameters which are gradable according to CTCAE v5.0, the grades will be derived 
using the local laboratory reference limits in analysis datasets. 
Table (4.2) 4 - Definition of CTCAE grade - Version 5.0 - Gradable parameters  
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium (mmol/l) – 
Hypernatremia 
]ULN;150] 
]150;155] 
]155;160] 
>160 
Sodium (mmol/l) - 
Hyponatremia 
[130;LLN[ 
- 
[120;130[ 
< 120 
Potassium (mmol/l) 
– Hyperkalemia 
]ULN;5.5] 
]5.5;6] 
]6;7] 
> 7 
Potassium (mmol/l) 
– Hypokalemia 
 
[3.0;LLN[ 
[2.5;3.0[ 
< 2.5 
Amylase (IU/L) - 
High 
>ULN – 1.5 x ULN 
>1.5 x ULN – 2 x 
ULN 
>2 x ULN – 5 x 
ULN 
> 5 x ULN 
Triacylglycerol 
Lipase (IU/L) - High  
>ULN – 1.5 x ULN 
>1.5 x ULN – 2 x 
ULN 
>2 x ULN – 5 x 
ULN 
> 5 x ULN 
Ionized calcium 
(mmol/l) - High 
]ULN;1.5] 
]1.5;1.6] 
]1.6;1.8] 
> 1.8 
Ionized calcium 
(mmol/l) - Low 
[1.0;LLN[ 
[0.9;1.0[ 
[0.8;0.9[ 
< 0.8 
Magnesium 
(mmol/l) - 
Hypermagnesemia 
]ULN;1.23] 
- 
]1.23;3.30] 
> 3.30 
Magnesium 
(mmol/l) - 
Hypomagnesemia 
[0.5;LLN[ 
[0.4;0.5[ 
[0.3;0.4[ 
< 0.3 
Albumin (g/l) - Low 
[30; LLN[ 
[20; 30[ 
< 20 
- 
Glucose (mmol/l) - 
Hypoglycemia 
[3.0;LLN[ 
[2.2;3.0[ 
[1.7;2.2[ 
< 1.7 
Total cholesterol 
(mmol/l) - High 
]ULN;7.75] 
]7.75;10.34] 
]10.34;12.92] 
> 12.92 
Triglycerides 
(mmol/l) - High 
[1.71;3.42] 
]3.42;5.7] 
]5.7;11.4] 
> 11.4 
Serum creatinine 
increased (umol/L) 
>ULN – 1.5 x ULN >1.5 x baseline – 3.0 
x baseline (if 
baseline available) 
OR 
>1.5 x ULN – 3.0 x 
ULN 
>3.0 x baseline (if 
baseline available) 
OR 
>3.0 x ULN – 6.0 x 
ULN 
>6.0 x ULN 
Total bilirubin 
increased (umol/L) 
>ULN – 1.5 x ULN 
if baseline is normal 
[≤ULN]; 
1.0 x baseline – 1.5 
x baseline if baseline 
is abnormal [>ULN] 
>1.5 x ULN – 3.0 x 
ULN if baseline is 
normal [≤ULN]; 
>1.5 x baseline – 3.0 
x baseline if baseline 
is abnormal [>ULN] 
>3.0 x ULN – 10.0 x 
ULN if baseline is 
normal [≤ULN]; 
>3.0 – 10.0 x 
baseline if baseline 
is abnormal [>ULN] 
>10.0 x ULN if 
baseline is normal 
[≤ULN]; 
>10.0 x baseline if 
baseline is abnormal 
[>ULN] 
CPK (IU/l) - high 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x 
ULN 
>5 x ULN – 10 x 
ULN 
> 10 x ULN 
Haemoglobin (g/dl) 
increased 
> ULN and increase 
from baseline ]0 ;2] 
(g/dl) 
> ULN and increase 
from baseline ]2 ;4] 
(g/dl) 
> ULN and increase 
from baseline > 4 
(g/dl) 
- 
Haemoglobin (g/dl) - 
Anemia 
[10;LLN[ 
[8;10[ 
< 8 
- 
White Blood Cells 
(g/l) - Low 
[3.0;LLN[ 
[2.0;3.0[ 
[1.0;2.0[ 
< 1.0 
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Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutrophils (g/l) - 
Low 
[1.5;LLN[ 
[1.0;1.5[ 
[0.5;1.0[ 
<0.5 
Lymphocytes (g/L) - 
Low 
[0.8;LLN[ 
[0.5;0.8[ 
[0.2;0.5[ 
<0.2 
Platelets (g/L) - Low 
[75;LLN[ 
[50;75[ 
[25;50[ 
<25 
aPTT (sec) - High 
>ULN – 1.5 x ULN 
>1.5 x ULN – 2.5 x 
ULN 
>2.5 x ULN 
- 
ALT increased 
(IU/L) 
>ULN – 3.0 x ULN 
if baseline is normal 
[≤ULN]; 
1.5 x baseline – 3.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>3.0 x ULN – 5.0 x 
ULN if baseline is 
normal[≤ULN]; 
>3.0 x baseline – 5.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>5.0 x ULN – 20.0 x 
ULN if baseline is 
normal [≤ULN]; 
>5.0 x baseline – 
20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
>20.0 x ULN if 
baseline is normal 
[≤ULN]; 
>20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
ALP increased 
(IU/L) 
>ULN – 2.5 x ULN 
if baseline is normal 
[≤ULN]; 2.0 x 
baseline – 2.5 x 
baseline if baseline 
is abnormal [ > 
ULN] 
>2.5 x ULN – 5.0 x 
ULN if baseline is 
normal [≤ULN]; 
2.5 x baseline – 5.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>5.0 x ULN – 20.0 x 
ULN if baseline is 
normal [≤ULN]; 
>5.0 x baseline – 
20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
>20.0 x ULN if 
baseline is normal 
[≤ULN]; 
>20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
AST increased 
(IU/L) 
 
>ULN – 3.0 x ULN 
if baseline is normal 
[≤ULN]; 
1.5 x baseline – 3.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>3.0 x ULN – 5.0 x 
ULN if baseline is 
normal [≤ULN]l; 
>3.0 x baseline – 5.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>5.0 x ULN – 20.0 x 
ULN if baseline is 
normal [≤ULN]; 
>5.0 x baseline – 
20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
>20.0 x ULN if 
baseline is normal 
[≤ULN]; 
>20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
GGT increased 
(IU/L) 
>ULN – 2.5 x ULN 
if baseline is 
normal[≤ULN]; 
2.0 x baseline – 2.5 
x baseline if baseline 
is abnormal [ > 
ULN] 
>2.5 x ULN – 5.0 x 
ULN if baseline is 
normal [≤ULN]; 
>2.5 x baseline – 5.0 
x baseline if baseline 
is abnormal [ > 
ULN] 
>5.0 x ULN – 20.0 x 
ULN if baseline is 
normal [≤ULN]; 
>5.0 x baseline – 
20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
>20.0 x ULN if 
baseline is normal 
[≤ULN]; 
>20.0 x baseline if 
baseline is abnormal 
[ > ULN] 
 
Any grade corresponds to a laboratory value with NCI-CTCAE version 5.0 grade 0, 1, 2, 3 or 
4. 
A grade 0 corresponds to a laboratory value within limit or reference range. 
The LOWEST value for a patient is defined as the lowest absolute laboratory value during the 
treatment period. 
A lowest value for a cycle is defined as the lowest laboratory value in that cycle. 
The time to lowest value is defined from the date of the first IMP intake to the sampling date 
of the lowest value. 
The time to lowest value in a cycle is defined from the first date of IMP intake in that cycle to 
the sampling date of the lowest value. 
The HIGHEST value for a patient is defined as the highest laboratory value during the 
treatment period. 
A highest value for a cycle is defined as the highest laboratory value in that cycle. 
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The time to highest value is defined from the date of the first IMP intake to the sampling date 
of the highest value. 
Urinary results 
The category positive includes results ‘+’, ‘++’ ‘+++’, and ‘++++’. 
The category negative corresponds to ‘Absent’ class. 
Creatinine clearance 
Creatinine clearance will be approximated by MDRD_GFR. This will be calculate as: 
MDRD_GFR (mL/min/1.73m2) = 175 x (serum creatinine in mg/dL)-1 154 x age-0 203 x 0.742 (if 
female) x 1.212 (if black race). 
Serum creatinine conversion: 
Serum creatinine (mg/mL) = Serum creatinine (µmol/L)/88.4. 
MDRD_GFR will be categorised in 4 categories: 
- Normal renal function (MDRD_GFR >90 mL/min/1.73m2). 
- Mild renal impairment (MDRD_GFR 60-90 mL/min/1.73m2). 
- Moderate renal impairment (MDRD_GFR 30-59 mL/min/1.73m2). 
- Severe (MDRD_GFR <30mL/mn/1.73m2). 
Worst value 
Worst value will be analysed as follow: 
▪ 
For the urinalysis parameters, the worst class will correspond to ‘Positive’ class, then 
‘Trace’ and finally ‘Negative’ will be considered as normal class. 
▪ 
For creatinine clearance, the worst class will correspond to “severe” category, then 
“moderate”, then “mild” and finally “normal”. 
▪ 
Baseline and post baseline worst grade for High and Low: 
o Low: If the result is below lower normal range limit, low =grade (for gradable 
parameter) or result (for non-gradable parameter), Else low=0. 
o High: If the result is above upper normal range limit, high =grade (for gradable 
parameter) or result (for non-gradable parameter), Else high =0. 
4.2.3.5. 
Vital signs, clinical examination and other observations related to safety 
4.2.3.5.1. 
Vital signs and clinical examination 
Worst value 
For ECOG, SBP, DBP and HR, the worst (highest) value will be derived. 
For Weight, SBP, DBP and HR, the worst (lowest) value will be derived. 
 
 
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Triplicates Baseline 
 
Record 
on 
treatment 
Emergence 
Abnormality 
ECG 
Emergence 
Significant 
Abnormality 
ECG 
All ECG within normal 
limit 
and 
Abnormality no 
significant 
Yes 
No 
All ECG within normal 
limit 
and 
Abnormality 
significant 
Yes 
Yes 
At least one line 
“Abnormality no 
significant “ and no line 
“Abnormality 
significant” 
and 
Abnormality 
significant 
No 
Yes 
No baseline 
or 
No post baseline Missing 
Missing 
If triplicate baseline is not missing and records on 
treatment are not missing and the combination is not 
covered by the previous cases. 
No 
No 
Maximum absolute prolongation during treatment period = max (Absolute prolongation 
during treatment period). 
Maximum change from baseline = Maximum absolute prolongation - Absolute prolongation 
at baseline. 
4.2.3.5.3. 
LVEF 
For this parameter, the worst value will correspond to the lowest measure. 
Analysis by grade according NCI-CTCAE version 5.0: 
Grade 0: other cases. 
Grade 2: LVEF [40 – 50%] or Change [-20; -10%]. 
Grade 3: LVEF [20 – 40%[ or Change < -20%]. 
Grade 4: LVEF < 20%. 
4.2.4. 
Biomarkers 
N/A. 
 
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5. REFERENCES 
Guidelines 
 
CTCAE (Common Terminology Criteria for Adverse Events) v5.0 
 
Guideline on Missing Data in Confirmatory Clinical Trials – Adopted by CHMP, June 2010, issued as 
EMA/CPMP/EWP/1776/99 Rev. 1. 
 
Guideline 
EMA 
“Guideline 
on 
evaluation 
of 
anticancer 
medicinal 
products 
in 
man” 
- 
EMA/CHMP/205/95/Rev.4-December 2012. 
 
 
 
 
 
 
ICH E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
 
 
 
 
 
 
 
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, issued 
as EMA/CHMP/ICH/435606/2012. 
 
 
 
 
 
 
ICH E3 - Structure and Content of Clinical Study Reports – Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5. 
 
 
 
 
 
 
ICH E9: Statistical Principles for Clinical Trials Final version – March 1998. 
Points to consider 
 
Points to Consider on Adjustment for Baseline Covariates – Adopted by CPMP, May 2003, issued as 
CPMP/EWP/2863/99. 
 
Points to Consider on Multiplicity Issues in Clinical Trials – Adopted by CPMP, September 2002, issued as 
CPMP/EWP/908/99. 
Bibliography 
 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR. et al. Diagnosis and management of AML in 
adults: 2017 ELN recommendations from an international expert panel. Blood, 2017;129 (4): 424-447. 
 
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