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

NCT02920541 | Completed Phase 1

• 3 other identifiers: CL1-055746-0022014-002559-24ISRCTN73586707
• Study Type: interventional
• Target: 48
• Locations: 2 countries
• Sites: 5

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.

Conditions

Acute Myeloid Leukaemia (AML); Myelodysplastic Syndrome (MDS)

Outcome Measures

Primary Outcomes (2)

• 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)

• 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 Outcomes (6)

• 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)

Study Arms (1)

S 055746

EXPERIMENTAL

Drug: S 055746

Interventions

S 055746 DRUG

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.

S 055746

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead
• ADIR, a Servier Group company: collaborator

Study Sites (5)

The Alfred Hospital

Melbourne, Australia

Location

Royal Melbourne Hospital

Parkville, Australia

Location

Institut Paoli Calmettes

Marseille, France

Location

Hôpital Saint Louis

Paris, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, France

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Study Officials

• Andrew Wei, MBBS, PhD

  The Alfred

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2016
• First Posted: September 30, 2016
• Study Start: January 1, 2015
• Primary Completion: May 24, 2018
• Study Completion: May 24, 2018
• Last Updated: May 24, 2019

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.

Locations

FR (3); AU (2)