Dose-escalation Study of Oral Administration of S 055746 in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome

Inclusion criteria

• Women or men aged >= 18 years
• Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML excluding acute promyelocytic leukaemia:

• with relapsed or refractory disease or
• > or = 65 years not previously treated for AML, who are not candidates for intensive chemotherapy or not candidates for standard chemotherapy
• Patients with cytologically confirmed and documented MDS or non proliferative Chronic Myelomonocytic Leukaemia (CMML) in relapse or refractory after previous treatment line including at least one hypomethylating agent therapy:

• with high or very high risk MDS and without established alternative therapy
• transformed to AML and without established alternative therapy
• Ability to swallow oral tablet(s)
• World Health Organization (WHO) performance status 0-2
• Circulating white blood cells < or = 30 x 10^9 /L and < or = 13 x10^9 for non proliferative CMML
• Adequate renal and hepatic functions
• Negative serum pregnancy test within 7 days prior to the first day of study drug administration
• Patients must use effective contraception
• Written informed consent

Exclusion criteria

• Foreseeable poor compliance to the study procedures
• Legally incapacitated person under guardianship or trusteeship
• Pregnant or breast-feeding women
• Participation in therapeutic interventional study involving investigational drug intake at the same time or within 2 weeks or at least 5 half-lives or patient already enrolled
• Previous treatment with a BH3 mimetic
• Patients who have not recovered to baseline or CTCAE< or = Grade 1 from toxicity due to all prior therapies received for the studied disease
• Any previous anti-leukaemic treatment for the studied disease within at least 5 half-lives or 2 weeks (hydroxycarbamide permitted)
• Any radiotherapy within 4 weeks before first intake (except palliative radiotherapy at localized lesions)
• Major surgery within 3 weeks before first intake of S 055746
• Allogenic stem cell transplant within 6 months before the first intake of S 055746 and for patients who still need immunosuppressive treatment
• Leukaemic leptomeningeal or leukaemic central nervous system involvement
• Concomitant uncontrolled infection, organ dysfunction or medical disease likely to interfere with evaluation of S 055746 safety or study outcome
• Human immunodeficiency virus (HIV) infection, hepatitis B or active hepatitis C infection
• Within 6 months prior to the first intake of S 055746, history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting, ischemic/haemorrhagic stroke, atrial fibrillation, digestive haemorrhagic risk, deep venous/arterial thromboembolic complication or bleeding diathesis
• Decreased Left Ventricular Ejection Fraction (LVEF)
• QTcF prolongation
• Patients who are receiving QT prolonging drug
• Coagulopathies with increased risk of bleeding complications
• Other malignancy within 2 years prior to the first intake
• Strong or moderate CYP3A4 inhibitors or inducers (treatment, food or drink products) within 7 days prior to the first intake
• Treatment highly metabolised by the CYP3A4 or CYP2D6 and/or with a narrow therapeutic index, multi-enzymes and/or OATP and/or P-gp substrates or herbal products within 7 days prior to the first intake.
• Patients receiving proton pump inhibitor
• Patients having received anticoagulant oral drugs, aspirin > 325 mg/day and antiplatelets within 7 days prior to first S 055746 intake