Clinical trial NCT02920541: Dose-escalation Study of Oral Administration of S 055746 in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukaemia (AML)
Myelodysplastic Syndrome (MDS)
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2016-09-30
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: During cycle 1 (21 days)
measure: Incidence of Adverse Events (AEs)
timeFrame: From first dose until 30 days after the last dose intake
Secondary outcomes:
measure: Plasma concentration of S 055746
timeFrame: 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
measure: The pharmacokinetic (PK) profile of S 055746: Area Under the Curve [AUC]
timeFrame: 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
measure: The PK profile of S 055746: Maximal Concentration [Cmax]
timeFrame: 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
measure: Best Response Rate (BRR)
timeFrame: Up to study completion (maximum of 3 years)
measure: Progression Free Survival (PFS)
timeFrame: 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)
measure: Event Free Survival (EFS)
timeFrame: 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)
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
Study officials:
affiliation: The Alfred
name: Andrew Wei, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References: