Acute Myeloid Leukaemia (AML), Myelodysplastic Syndrome (MDS)
Conditions
Brief summary
The purpose of this study is to determine the safety profile and tolerability of S 055746 in patients with AML, and high or very high risk MDS, in terms of Dose-Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD) and determine the Recommended Phase 2 Dose (RP2D) through safety profile (DLT, MTD), PK profile, PD profile and preliminary efficacy.
Interventions
DRUGS 055746
S 055746, per os administration, from 50 to 2000 mg once a day during a 21-day cycle. Participants will receive 21-day cycles of treatment until a discontinuation criterion is met.
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | During cycle 1 (21 days) | MTD is the highest drug dosage that is unlikely (\<25% posterior probability) to cause DLT in more than 33% of the treated patients in the first cycle of S 055746 treatment. |
| Incidence of Adverse Events (AEs) | From first dose until 30 days after the last dose intake | Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes |
Secondary
| Measure | Time frame |
|---|---|
| The PK profile of S 055746: Maximal Concentration [Cmax] | Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8 |
| Best Response Rate (BRR) | Up to study completion (maximum of 3 years) |
| Plasma concentration of S 055746 | Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8 |
| Event Free Survival (EFS) | From date of inclusion until the date of progression or date of death or discontinuation of treatment, whichever occurs first, assessed up to study completion (maximum of 3 years) |
| Progression Free Survival (PFS) | From date of inclusion until the date of progression or date of death, whichever occurs first, assessed up to study completion (maximum of 3 years) |
| The pharmacokinetic (PK) profile of S 055746: Area Under the Curve [AUC] | Pre-dose on Cycle 1 Day 1 (C1D1), C1D2, C1D3, C1D8, C1D9, C2D1 ; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10-12 hours post-dose on C1D1, C1D8 |
Countries
Australia, France
Outcome results
None listed