A Study to Evaluate S227928 as a Single Agent and in Combination With Venetoclax in Patients With R/R AML, MDS/AML, or CMML

Key Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Women of childbearing potential (WOCBP) must use a highly effective method of birth control during study treatment and at least 6 months after the last dose of Investigational Medicinal Product (IMP). In case of the use of oral contraception, women should have been on a stable dose of the same contraceptive drug (i.e., same active principle) for at least 3 months prior to the first IMP administration.
* Male participants with WOCBP partners must use a condom during the study and for at least 3 months after the last dose of IMP. In addition, contraception should be considered for their female partners. Contraceptive measures do not apply if the participant is sterile, vasectomised or sexually abstinent. Sperm donation will not be allowed during the study and for at least 3 months after the last dose of IMP.
* Patients with pathologically confirmed AML, MDS/AML, or CMML as defined by the World Health Organization (WHO) 2022 classification or ICC, who have been previously treated with at least one prior standard treatment and have relapsed and/or refractory disease.

  1. Patients must not be candidates for further standard therapy,
  2. Treatment with agents for lower risk MDS such as erythropoietin or luspatercept are not considered anticancer therapies.
* Circulating leukocytes \< 10 x 109/L (use of hydroxycarbamide before study drug initiation is allowed to achieve this inclusion criterion).
* Adequate renal function within 7 days before study enrollment defined as:

  a. Calculated creatinine clearance (determined by the modification of diet in renal disease \[MDRD\] equation) ≥ 60 mL/min
* Adequate hepatic function within 7 days before study enrollment defined as:

  1. Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN),
  2. Total bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert's syndrome, who may be included if their total bilirubin is ≤ 3.0 x ULN and their direct bilirubin is ≤ 1.5 x ULN.

Key Exclusion Criteria:

* Pregnant or lactating women.
* WOCBP tested positive in a serum pregnancy test within 7 days prior to the first day of IMP administration.
* Legally incapacitated person under guardianship or trusteeship.
* Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 5.0 \[CTCAE v5.0\]) from acute non-hematologic toxicities (to ≤ Grade 2 for neuropathy) due to previous therapy, prior to screening.
* Diagnosis of myeloproliferative neoplasms (MPNs) or other non-CMML MDS/MPNs as defined by the WHO 2022 classification
* Diagnosis of acute promyelocytic leukemia (French-American-British \[FAB\] M3 classification).
* Diagnosis of acute leukemia of mixed or ambiguous lineage or histiocytic/dendritic cell neoplasms defined by the WHO 2022 classification
* Uncontrolled infections requiring systemic antibiotics and/or antifungal agents as per investigator's judgment. Patients receiving prophylactic antibiotics and/or antifungal agents are eligible for this study.
* Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy, or with detectable HBV viral load.
* Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load.
* Human immunodeficiency virus (HIV) seropositive with any of the following:

  1. CD4+ T-cell (CD4+) counts \< 350 cells/µL
  2. Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening
  3. Not on antiretroviral therapy, or on antiretroviral therapy for \< 6 weeks at the time of Day 1 in Cycle 1
  4. HIV viral load ≥ 400 copies/mL
* Participants with a known clinically significant cardiovascular disease or condition, including

  1. Uncontrolled arterial hypertension per the investigator's judgment
  2. New York Heart Association class III or IV congestive heart failure
  3. Congenital or substance-induced long QT defined as heart rate-corrected QT (QTc) interval \>450 ms for males and \>470 ms for females according to Fridericia's formula
  4. Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible)
  5. Severe uncorrected conduction disturbances (e.g., 3rd degree heart block). Patients with severe conduction disturbances corrected by a pacemaker are eligible
  6. Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction), coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration
  7. Troponin I \> ULN or troponin T \> ULN if troponin I cannot be assessed
  8. Any factors that could increase the risk of QTc interval prolongation or risk of arrhythmic events such as heart failure, family history of QT syndrome, or family history of unexplained sudden death under 40 years of age
* Known active central nervous system involvement by AML, MDS/AML, or CMML.
* Coagulation disorders or abnormalities that may increase the risk of bleeding complications according to investigator's judgment (e.g., disseminated intravascular coagulation).
* Any clinically significant medical condition (e.g., organ dysfunction, gastric ulcer) or laboratory abnormality likely to jeopardize the patient's safety or to interfere with the conduct of the study.
* Major surgery within 4 weeks before the first IMP administration, or patients who have not recovered from the acute effects of surgery.
* Allogeneic stem cell transplantation (SCT) within 3 months before the first dose of IMP

  a. Patients cannot be receiving any immunosuppressive treatment, except for corticosteroids used as physiologic replacement doses up to the equivalent of 10 mg of oral prednisone
* Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: 1) malignancies that were treated curatively, which have not recurred within 3 years prior to study entry and do not require further treatment; 2) completely resected basal and squamous cell skin cancers; 3) any malignancy considered to be indolent and that has never required anticancer therapy; and 4) completely resected carcinoma in situ of any type.
* History of severe allergic or anaphylactic reactions to BH3 mimetics (including venetoclax) or to any excipients of S227928.
* Any previous anticancer treatment for the studied disease within 2 weeks or at least 5 half-lives (whichever is longer) prior to first dose of IMPs (except for hydroxycarbamide). In case of investigational biologic agents with a long half-life, such as immune checkpoint or bispecific antibodies, a flat wash-out period of 28 days will be acceptable. Participation in non-interventional registries or epidemiological studies is allowed. Hormonal therapies are not considered anticancer treatments for eligibility purposes.
* Any cellular therapies (e.g., NK or CAR T cells) within 100 days prior to first dose of IMP.
* Any radiotherapy within 2 weeks before the first dose of IMPs (except for palliative radiotherapy to localized lesions, i.e., chloromas).
* Any drugs known to prolong the QT interval and induce Torsade de pointes (TdP) within 7 days prior to the first administration of IMP.
* Dose Escalation Arm A ONLY: Although participants may be treated with strong inhibitors of CYP3A4 or of CYP2C8, they may not be treated with medications that are strong inhibitors of both CYP3A4 and CYP2C8, or with separate medications that when combined would cause strong inhibition of these two enzymes. In addition, participants may not be treated with a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2C8 and/or a moderate inhibitor of P-gp. These prohibitions begin 7 days prior to the start of IMP and continue for the entire duration of treatment. Triazole antifungal agents may be used, but only if they are in agreement with the criteria described above (i.e., they must not be dual strong inhibitors of both CYP3A4 and CYP2C8 or strong inhibitors of CYP3A4 and moderate inhibitors of either CYP2C8 or P-gp).
* Dose Escalation Arm B and Dose Expansion ONLY: a malabsorption syndrome or other condition that precludes enteral route of administration.
* Dose Escalation Arm B and Dose Expansion ONLY: Both moderate and strong inhibitors of CYP3A4 are prohibited, beginning 7 days prior to the start of IMP and continuing for the entire duration of treatment.
* Dose Escalation Arm B and Dose Expansion ONLY: Both moderate and strong CYP3A4 inducers are prohibited, beginning 14 days before the start of IMP and continuing for the entire duration of treatment.
* Dose Escalation Arm B and Dose Expansion ONLY: treatment with P-gp and BCRP inhibitors; or with medications with a narrow therapeutic index (NTIs) which are substrates of P-gp or BCRP; or with OATP1B1 substrates that cannot be discontinued 7 days before and during study treatment