The purpose of this study is to determine the safety profile, tolerability and the Recommended Phase 2 Dose of the combination S64315 with venetoclax in patients with Acute Myeloid Leukaemia.

Inclusion Criteria:

1. Male or female aged ≥ 18 years;

2. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by World Health Organization (WHO) 2016 classification (Arber, 2016), excluding acute promyelocytic leukaemia (APL, French-American British M3 classification):

   • With relapsed or refractory disease without established alternative therapy or
   • Secondary to MDS treated at least by hypomethylating agent and without established alternative therapy or
   • ≥ 65 years not previously treated for AML and who are not candidates for intensive chemotherapy nor candidates for established alternative therapy

3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

4. Able to comply with study procedures

5. Adequate renal function within 7 days before the inclusion of the patient defined as:

   • Serum creatinine ≤ 1.5 x ULN (upper normal limit) or calculated creatinine clearance (determined by MDRD) > 50 mL/min/1.73m2

6. Adequate hepatic function within 7 days before the inclusion of the patient defined as:

   • AST and ALT ≤ 1.5 x ULN
   • Total serum 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

Exclusion Criteria:

1. Participant already enrolled and treated in the study
2. Pregnancy, breastfeeding or possibility of becoming pregnant during the study
3. Participation in another interventional study requiring investigational treatment intake at the same time or within 2 weeks or at least 5 halflives (whichever is longer) prior to first dose of IMP (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 antibodies, bispecific antibodies a flat wash-out of 28 days will be acceptable
4. Presence of ≥ CTCAE Grade 2 toxicity (except alopecia of any grade) due to prior cancer therapy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE, version 4.03).
5. Known carriers of HIV antibodies
6. Known history of significant liver disease
7. Uncontrolled hepatitis B or C infection
8. Known active acute or chronic pancreatitis
9. History of myocardial infarction (MI), unstable angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
10. Any factors that could increase the risk of QTc prolongation or risk of arrhythmic events.

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

After Marketing Authorisation in EEA or US if the study is used for the approval.

Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.