Condition category
Cancer
Date applied
01/08/2014
Date assigned
04/09/2014
Last edited
16/01/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Not provided at time of registration and not expected to be available in the future

Trial website

Contact information

Type

Scientific

Primary contact

Prof Andrew Wei

ORCID ID

Contact details

Department of Haematology
The Alfred Hospital Commercial Road
Melbourne
VIC 3004
Australia

Additional identifiers

EudraCT number

2014-002559-24

ClinicalTrials.gov number

NCT02920541

Protocol/serial number

CL1-055746-002

Study information

Scientific title

Phase I dose-escalation study of the orally administrered selective Bcl-2 inhibitor S055746 as monotherapy for the treatment of patients with Acute Myeloid Leukaemia (AML) or high or very high risk Myelodysplastic Syndrome (MDS)

Acronym

Study hypothesis

To determine the safety profile and tolerability of S 055746 and establish the recommended Phase II dose.

Ethics approval

Ethics approval was obtained before recruitment of the first participants

Study design

Phase I dose-escalation study

Primary study design

Interventional

Secondary study design

Dose-escalation study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not provided at time of registration

Condition

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

Intervention

Current interventions as of 13/01/2017:
Film-¬coated tablets containing 50 mg or 100 mg of S055746. This trial is a dose escalation trial. The first daily dose tested will be 100 mg, and then a panel of daily doses from 50 to 2000 mg could be tested. Treatment duration for the participant is until evidence of progressive disease, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or if clinically indicated after discussion between investigator and the sponsor on a case by case basis.

Previous interventions:
Film-coated tablets containing 50 mg or 100mg of S055746. This trial is a dose escalation trial. A modified version of the Continual Reassessment Method (mCRM) will be used for dose allocation process. The first daily dose tested will be 100 mg, and then a panel of daily doses from 50 to 1000 mg could be tested according to the dose allocation process of the mCRM. Doses over 1000 mg and intermediate doses could be proposed depending on available results during the study. Treatment duration for the participant is until evidence of treatment failure, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or if clinically indicated after discussion between investigator and the sponsor on a case by case basis

Intervention type

Drug

Phase

Phase I

Drug names

S055746

Primary outcome measures

Current primary outcome measures as of 13/01/2017:
1. Dose Limiting Toxicities in cycle 1
2. Maximum Tolerated Dose, defined as 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
3. Safety profile at each visit, assessed by adverse events monitoring, laboratory tests, vital signs and performance status, clinical examination and ECG parameters

Previous primary outcome measures:
1. Dose Limiting Toxicities in cycle 1
2. Maximum Tolerated Dose defined as the highest dose administered in the study at which the incidence of DLT is 30%
3. Safety profile at each visit assessed by Adverse events monitoring, laboratory tests, vital signs and performance status, clinical examination and ECG parameters

Secondary outcome measures

1. Pharmacokinetics parameters on blood sample during cycles 1 and 2
2. PD parameters on blood, BMA and biospy if available from cycle 1 to cycle 3 and in any time in case of suspicion of disease progression optional pharmacogenomics analysis on Cycle 1, D1 pre-dose
3. Preliminary anti-leukaemic activity of S055746 throughout the study (blood, BMA and biopsy if available)

Overall trial start date

01/01/2015

Overall trial end date

31/08/2018

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 13/01/2017:
1. Women or men aged >= 18 years
2. Patients with cytologically confirmed and documented de novo, secondary or therapy¬related AML excluding acute promyelocytic leukaemia :
2.1. With relapsed or refractory disease without established alternative therapy or
2.2. > or = 65 years not previously treated for AML, who are not candidates for intensive chemotherapy or not candidates for standard chemotherapy
3. Patients with cytollogically confirmed and documented MDS or non-proliferative Chronic Myelomonocytic Leukaemia (CMML) patients, in relapse or refractory after previous treatment line including at least one hypomethylating agent (5-azacytidine or decitabine):
3.1. With high or very high risk MDS and without established alternative therapy
3.2. Transformed to AML and without established alternative therapy
4. Ability to swallow oral tablet(s)
5. WHO performance status 0-2
6. Circulating white blood cells < or = 30 x 10^9 /L and < or = 13 x 10^9/L for non-proliferative CMML
7. Adequate renal and hepatic functions
8. Negative serum pregnancy test within 7 days prior to the first day of study drug administration
9. Patients must use effective contraception
10. Written informed consent

Previous inclusion criteria:
1. Women or men aged >= 18 years
2. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML excluding APL, with relapsed or refractory disease or > or = 65 years not previously treated, who are not candidates for intensive chemotherapy or not candidates for standard chemotherapy
3. Patients with cytollogically confirmed and documented high or very high risk myelodysplastic syndrome who have failed prior hypomethylating therapy
4. WHO performance status 0-2
5. Circulating white blood cells < or = 30 x 10^9 /L
6. For MDS patients:
6.1. Platelets count > 25 10^9/L
6.2. Neutrophils > 0.5 10^9/L
7. Acceptable coagulation parameters according to local laboratory
8. Adequate renal and hepatic functions
9. Negative serum pregnancy test within 7 days prior to the first day of study drug administration
10. Patients must use effective contraception

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

60 to 80 patients

Participant exclusion criteria

Current exclusion criteria as of 13/01/2017:
1. Foreseeable poor compliance to the study procedures
2. Legally incapacitated person under guardianship or trusteeship
3. Pregnant or breastfeeding women
4. 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
5. Previous treatment with a BH3 mimetic
6. Patients who have not recovered to baseline or CTCAE< or = Grade 1 from toxicity due to all prior therapies received for the studied disease
7. Any previous anti¬leukaemic treatment (AML, high or very high risk MDS) within at least 5 half-lives or 2 weeks prior to the study entry except for hydroxyurea
8. Any radiotherapy within 4 weeks before first intake
9. Major surgery within 3 weeks before first intake of S 055746
10. Allogenic stem cell transplant within 6 months before the first intake of S 055746 and for patients who still need immunosuppressive treatment
11. Leukaemic leptomeningeal or leukaemic central nervous system involvement
12. Concomitant uncontrolled infection, organ dysfunction or medical disease likelty to interfere with evaluation of S 055746 safety or study outcome
13. Human immunodeficiency virus (HIV), hepatitis B or active hepatitis C infection
14. 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/haemorragic stroke, atrial fibrillation, digestive haemorrhagic risk, deep venous/arterial thromboembolic complication or bleeding diathesis
15. Decreased Left Ventricular Ejection Fraction (LVEF)
16. QTcF prolongation
17. Patients who are receiving QT prolonging drug
18. Coagulopathies with increased risk of bleeding complications
19. Other malignancy within 2 years prior to the first intake
20. Strong or moderate CYP3A4 inhibitors or inducers (treatment, food or drink products) within 7 days prior to the first intake
21. Treatment highly metabolised by the CYP3A4 and with a narrow therapeutic index within 7 days prior to the first intake.
22. Patients receiving proton pump inhibitor

Previous exclusion criteria:
1. Pregnant or breastfeeding women
2. Involvement in therapeutic interventional study at the same time or within 2 weeks prior to first S 055746 intake or patient already enrolled in the study
3. Previous treatment with a BH3 mimetic
4. Patients who have not recovered to baseline or CTCAE< or = Grade 1 from toxicity due to all prior therapies
5. Any previous anti-leukaemic treatment (AML, high or very high risk MDS) within at least 5 half lives or 2 weeks prior to the study entry except for hydroxyurea
6. Any radiotherapy within 4 weeks before first intake
7. Major surgery within 3 weeks before first intake of S 055746
8. Allogenic stem cell transplant within 6 months before the first intake of S 055746 and for patients who still need immunosuppressive treatment
9. Leukaemic leptomeningeal or leukaemic central nervous system involvement
10. Concomitant uncontrolled infection, organ dysfunction or medical disease likelty to interfere with evaluation of S 055746 safety or study outcome
11. Human immunodeficiency virus (HIV)
12. 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/haemorragic stroke, atrial fibrillation, digestive haemorrhagic risk, deep venous/arterial thromboembolic complication or bleeding diathesis
13. QTc prolongation
14. LVEF assessed by echocardiography or Multi-Gated Acquisition scan (MUGA scan)
15. Treatment, food or drink products known to inhibit or induce CYP3A4 within 7 days prior to the first intake
16. Treatment highly metabolised by the CYP3A4 and with a narrow therapeutic index within 7 days prior to the first intake.

Recruitment start date

01/01/2015

Recruitment end date

01/02/2018

Locations

Countries of recruitment

Australia, France

Trial participating centre

Department of Haematology
Melbourne
VIC 3004
Australia

Trial participating centre

Royal Melbourne Hospital
300 Grattan St Parkville
Melbourne
VIC 3050
Australia

Trial participating centre

Institut Paoli Calmettes
232, boulevard Sainte Marguerite
Marseille
13009
France

Trial participating centre

Hôpital Lyon-Sud
165 Chemin du Grand Revoyet
Pierre-Bénite
69310
France

Trial participating centre

Hôpital Saint-Louis
1 Avenue Claude Vellefaux
Paris
75010
France

Sponsor information

Organisation

Institut de Recherches Internationales Servier (France)

Sponsor details

50 rue Carnot
Suresnes
92284
France

Sponsor type

Industry

Website

http://www.servier.com/

Funders

Funder type

Industry

Funder name

ADIR

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The trialists will comply with regulatory requirements

IPD sharing plan
The datasets generated during and/or analysed during the current study are/will be available upon request after Marketing Authorisation has been granted

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

13/01/2017: The following changes were made to the trial record: 1. The recruitment end date was changed from 01/01/2017 to 01/02/2018. 2. The overall trial end date was changed from 01/01/2017 to 31/08/2018. 3. The funder was changed from Institut de Recherches Internationales Servier to ADIR.