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

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Completed

CT.gov ID

NCT02920541

Collaborator

ADIR, a Servier Group company (Industry)

Enrollment

Locations

Arm

40.7

Duration (Months)

9.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukaemia (AML) Myelodysplastic Syndrome (MDS)	Drug: S 055746	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

48 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Study Start Date :

Jan 1, 2015

Actual Primary Completion Date :

May 24, 2018

Actual Study Completion Date :

May 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: S 055746	Drug: S 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.

Arm

Intervention/Treatment

Experimental: S 055746

Drug: S 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.

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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]
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]
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)]
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)]
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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	The Alfred Hospital	Melbourne	Australia
2	Royal Melbourne Hospital	Parkville	Australia
3	Institut Paoli Calmettes	Marseille	France
4	Hôpital Saint Louis	Paris	France
5	Centre Hospitalier Lyon Sud	Pierre Bénite	France