Myelodysplastic Syndrome (MDS) Clinical Trial
Official title:
Phase I Dose-escalation Study of the Orally Administered Selective Bcl-2 Inhibitor S 055746 as Monotherapy for the Treatment of Patients With Acute Myeloid Leukaemia (AML) or High or Very High Risk Myelodysplastic Syndrome (MDS)
Verified date | May 2019 |
Source | Servier |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 48 |
Est. completion date | May 24, 2018 |
Est. primary completion date | May 24, 2018 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility |
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 |
Country | Name | City | State |
---|---|---|---|
Australia | The Alfred Hospital | Melbourne | |
Australia | Royal Melbourne Hospital | Parkville | |
France | Institut Paoli Calmettes | Marseille | |
France | Hôpital Saint Louis | Paris | |
France | Centre Hospitalier Lyon Sud | Pierre Bénite |
Lead Sponsor | Collaborator |
---|---|
Institut de Recherches Internationales Servier | ADIR, a Servier Group company |
Australia, France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Maximum Tolerated Dose (MTD) | 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. | During cycle 1 (21 days) | |
Primary | Incidence of Adverse Events (AEs) | Characterized by severity and seriousness of AEs, laboratory abnormalities and other safety parameters such as electrocardiogram (ECG) changes | From first dose until 30 days after the last dose intake | |
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | 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 | ||
Secondary | Best Response Rate (BRR) | Up to study completion (maximum of 3 years) | ||
Secondary | 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) | ||
Secondary | 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) |
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