Phase I dose-escalation study of oral administration of S055746 in patients with Acute Myeloid Leukaemia or Myelodysplastic Syndrome
- Conditions
- Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS)Cancer
- Registration Number
- ISRCTN73586707
- Lead Sponsor
- Institut de Recherches Internationales Servier (France)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Stopped
- Sex
- All
- Target Recruitment
- 80
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
Current exclusion criteria as of 14/03/2018:
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 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.
22. Patients receiving proton pump inhibitor
23.Patients having received anticoagulant oral drugs, aspirin > 325 mg/day and antiplatelets within 7 days prior to first S 055746 intake
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <br> Current primary outcome measures as of 13/01/2017:<br> 1. Dose Limiting Toxicities in cycle 1<br> 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<br> 3. Safety profile at each visit, assessed by adverse events monitoring, laboratory tests, vital signs and performance status, clinical examination and ECG parameters<br><br> Previous primary outcome measures:<br> 1. Dose Limiting Toxicities in cycle 1<br> 2. Maximum Tolerated Dose defined as the highest dose administered in the study at which the incidence of DLT is 30%<br> 3. Safety profile at each visit assessed by Adverse events monitoring, laboratory tests, vital signs and performance status, clinical examination and ECG parameters<br>
- Secondary Outcome Measures
Name Time Method <br> Current Secondary Outcome measures as of 14/03/2018:<br> 1. Pharmacokinetics parameters on blood sample during cycles 1 and 2<br> 2. Preliminary anti-leukaemic activity of S055746 throughout the study (blood, BMA and biopsy if available)<br><br> Previous Secondary Outcome Measures:<br> 1. Pharmacokinetics parameters on blood sample during cycles 1 and 2<br> 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<br> 3. Preliminary anti-leukaemic activity of S055746 throughout the study (blood, BMA and biopsy if available)<br>