Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02920541




Registration number
NCT02920541
Ethics application status
Date submitted
23/08/2016
Date registered
30/09/2016
Date last updated
24/05/2019

Titles & IDs
Public title
Dose-escalation Study of Oral Administration of S 055746 in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome
Scientific 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)
Secondary ID [1] 0 0
2014-002559-24
Secondary ID [2] 0 0
CL1-055746-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia (AML) 0 0
Myelodysplastic Syndrome (MDS) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - S 055746

Experimental: S 055746 -


Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Tolerated Dose (MTD)
Timepoint [1] 0 0
During cycle 1 (21 days)
Primary outcome [2] 0 0
Incidence of Adverse Events (AEs)
Timepoint [2] 0 0
From first dose until 30 days after the last dose intake
Secondary outcome [1] 0 0
Plasma concentration of S 055746
Timepoint [1] 0 0
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 outcome [2] 0 0
The pharmacokinetic (PK) profile of S 055746: Area Under the Curve [AUC]
Timepoint [2] 0 0
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 outcome [3] 0 0
The PK profile of S 055746: Maximal Concentration [Cmax]
Timepoint [3] 0 0
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 outcome [4] 0 0
Best Response Rate (BRR)
Timepoint [4] 0 0
Up to study completion (maximum of 3 years)
Secondary outcome [5] 0 0
Progression Free Survival (PFS)
Timepoint [5] 0 0
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 outcome [6] 0 0
Event Free Survival (EFS)
Timepoint [6] 0 0
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
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/01/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
24/05/2018
Sample size
Target
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
The Alfred Hospital - Melbourne
Recruitment hospital [2] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
- Melbourne
Recruitment postcode(s) [2] 0 0
- Parkville
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Marseille
Country [2] 0 0
France
State/province [2] 0 0
Paris
Country [3] 0 0
France
State/province [3] 0 0
Pierre Bénite

Funding & Sponsors
Primary sponsor type
Other
Name
Institut de Recherches Internationales Servier
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
ADIR, a Servier Group company
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02920541
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Andrew Wei, MBBS, PhD
Address 0 0
The Alfred
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02920541