Phase I, international, multicentre, open-label, non-randomised, non-comparative study of intravenously administered S64315, a Mcl1-inhibitor, in patients with Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS)
- Conditions
- cancer of the bloodleucaemia10024324
- Registration Number
- NL-OMON48784
- Lead Sponsor
- Servier R&D Benelux
- Brief Summary
Trial never started
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 8
1. Male or female aged * 18 years old.
2. Patients with cytologically confirmed and documented de novo, secondary or
therapy-related AML excluding acute promyelocytic leukaemia:
* with relapsed or refractory disease without established alternative therapy or
* secondary to MDS treated at least by hypomethylating agent and without
established alternative therapy or
* > 65 years not previously treated for AML and who are not candidates for
intensive chemotherapy nor candidates for established alternative chemotherapy
Or
Patients with cytologically confirmed and documented MDS in relapse or
refractory after previous treatment line including at least one
hypomethylating agent and have *10% bone marrow blasts and who are not
candidates for any established alternative therapy.
3. ECOG performance status 0 to 2
4. Circulating white blood cells < 10.109/L
5. Adequate renal function
6. LDH < 2 x ULN
7. Adequate hepatic function
8. Serum CK/CPK *2.5 ULN
9. female participants of childbearing potential and male participants with
partners of childbearing potential must use an highly effective method of birth
control, as well as their partners, starting at least 1 month prior to the
first S64315 administration and lasting at least 30 days after the last dose of
S64315.
10. Women of childbearing potential must have been tested negative in a serum
pregnancy test within 7 days prior to the first day of test drug administration.
11. Written informed consent prior any study-specific procedure
12. Unlikely to cooperate in the study.
13. Participant already enrolled in the study who has received at least one
S64315 infusion.
14. Pregnancy, breastfeeding or possibility of becoming pregnant during the
study
15. Participation in another interventional study requiring investigational
treatment intake within 2 weeks or at least 5 half-lives (whichever is longer)
prior to first dose of S64315 (participation in non-interventional registries
or epidemiological studies is allowed).
16. Presence of * CTCAE grade 2 toxicity (except alopecia of any grade) due to
prior cancer therapy, according to NCI-CTCAE, version 4.03
17. Known carriers of HIV antibodies,
18. Known history of significant liver disease,
19. Uncontrolled hepatitis B or C infection,
20. Known active or chronic pancreatitis,
21. History of myocardial infarction (MI), angina pectoris, coronary artery
bypass graft (CABG) within 6 months prior to starting study treatment,
22. Clinically significant cardiac arrhythmias, complete left bundle branch
block, high-grade AV block
23. Troponin (I/T) > ULN,
24. LVEF < 50% as assessed by echocardiogram (ECHO) or Multi-Gated Acquisition
scan (MUGA scan),
25. QTc prolongation defined as a QTc interval (corrected with Fredericia) >
450 ms for male and > 470 ms for female,
26. Clinically active severe skin diseases,
27. Any clinically significant medical condition or laboratory abnormality
likely to jeopardize the patient*s safety or to interfere with the conduct of
the study, in the investigator*s opinion,
28. Active central nervous system disease,
29. Unresolved diarrhea CTCAE grade 2 or higher or presence of medical
condition associated with chronical diarrhea (such as irritable bowel syndrome,
inflammatory bowel disease)
30. Patients with coagulopathy that will increase the risk of bleeding
complications according to investigator*s judgment
31. Allogenic stem cell transplant within 3 months before the first dose of
S64315 and for patients who still receive immunosuppressive treatment,
32. Major surgery (involving a risk to the life of the patient) within 2 weeks
before the first dose of S64315, or patients who have not recovered from side
effects of the surgery,
33. Any previous anti-neoplastic treatment for the studied disease at least 5
half-lives of this treatment prior to first dose of S64315 (except for
hydroxycarbamide),
34. Malignant disease, other than that being treated in this study. Exceptions
to this exclusion include the following: malignancies that were treated
curatively and have not recurred within 2 years prior to study entry;
completely resected basal cell and squamous cell skin cancers; any malignancy
considered to be indolent and that has never required therapy; and completely
resected carcinoma in situ of any type,
35. Any radiotherapy within 2 weeks before the first dose of S64315 (except for
palliative radiotherapy at localised lesions),
36. Prior treatment with an Mcl-1 inhibitor,
37. Patients receiving treatment with medications listed in Section 6.3.1 and
that cannot be discontinued at least 1 week prior to start of the study
treatment and during the study treatment period.
38. Patients with known hypersensitivity to 64315 including eggs, to soybean or
to the excipients of the liposomal vehicle
39. Patients re
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>To determine the safety profile and tolerability of S64315 in patients with<br /><br>AML, and MDS and to determine the RP2D. (DLT during the first cycle of<br /><br>treatment, incidence and severity of AEs and SAEs, lab results, vital signs,<br /><br>ECG parameters, LVEF assessment, dose interruptions or reductions,..)</p><br>
- Secondary Outcome Measures
Name Time Method <p>The pharmacokinetics profile of S64315 will be determined and the preliminary<br /><br>anti-neoplastic activity of S64315 will be assessed.<br /><br>The pharmacodynamics profile of S64315 will be assessed (biological activity of<br /><br>S64315: kinetic assessment of blast reduction), the relation between the<br /><br>expression of Bcl-2 family members in blasts and the anti-neoplastic activity<br /><br>of S64315 (Bcl-2 family members expression), the relationship between the<br /><br>anti-neoplastic activity of S64315 and genomic aberrations in the Bcl-2 gene<br /><br>family and other cancer related genes (somatic alterations and expression of<br /><br>Bcl-2 gene family and a panel of cancer-related genes). Identification of<br /><br>genetic abnormalities potentially induced by S64315 (karyotype analysis).</p><br>