A study to evaluate S227928 as a Single Agent and in Combination with Venetoclax in Patients with R/R AML, MDS/AML, or CMML

Prior treatment

• Failure to recover to ≤ Grade 1 (Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0]) from acute non-hematologic toxicities due to previous therapy, prior to screening.
• For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion), those with a malabsorption syndrome or other condition that precludes enteral route of administration.
• For all participants receiving S227928 (as a single agent and in combination with Venetoclax): 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.
• Participants previously treated with S227928 in Arm A will not be eligible for treatment in Arm B.
• For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): Both moderate and strong CYP3A4 inducers are prohibited, beginning 14 days before the start of IMP and continuing for the entire duration of treatment.
• For all participants receiving S227928 in combination with venetoclax (i.e., Arm B dose escalation and dose expansion): BCRP inhibitors, and medications which are substrates of P-gP, BCRP, or OATP1B1 with a narrow therapeutic index (NTIs) are prohibited, beginning 7 days prior to the start of IMP and continuing for the entire duration of treatment. If concomitant use of P-gp substrate is unavoidable, its dosing should be done at least 6 hours apart from venetoclax.
• 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.

Lab values

• Participants with a known clinically significant cardiovascular disease or condition, including: a. Uncontrolled arterial hypertension per the investigator’s judgment, b. New York Heart Association (NYHA) class III or IV congestive heart failure, c. Congenital or substance-induced long QT defined as heart rate-corrected QT (QTc) interval > 470 ms according to Fridericia’s formula, d. Uncontrolled cardiac arrhythmia (e.g., participants with rate-controlled atrial fibrillation are eligible), e. Severe uncorrected conduction disturbances (e.g., 3rd degree heart block). Patients with severe conduction disturbances corrected by a pacemaker are eligible, f. Acute coronary syndrome (including unstable angina pectoris, acute myocardial infarction),coronary angioplasty or bypass grafting within 6 months prior to the first IMP administration, g. Troponin I > ULN or troponin T > ULN if troponin I cannot be assessed, h. 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.

Other

• 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.
• Known active central nervous system involvement by AML, MDS/AML, or CMML

• Adult participant (must be ≥ 18 years of age or according to local requirements).
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.except for European Countries where only ECOG performance status of 0 and 1 will be allowed.
• Written informed consent must be obtained prior to any study-specific procedures.
• Patients with pathologically confirmed AML, MDS/AML, or CMML as defined by the WHO 2022 classification or ICC, who have been previously treated with at least one prior standard treatment and have relapsed and/or refractory disease: a. Patients must not be candidates for further standard therapy, b. Treatment with agents for lower risk MDS such as erythropoietin or luspatercept are not considered anticancer therapies. c. Patients with R/R MDS with bone marrow blast count that does not meet ICC criteria for MDS/AML (i.e., bone marrow blast count <10%) will not be eligible for this study.
• Circulating leukocytes < 10 x 10^9/L (use of hydroxycarbamide before study drug initiation is allowed to achieve this inclusion criterion).
• Adequate renal and hepatic function within 7 days before study enrollment.