Patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or secondary acute myeloid leukemia (sAML) before stem cell transplantation MedDRA version: 20.1 Level: LLT Classification code 10024329 Term: Leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Venclyxto
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Venetoclax
CAS Number: 1257044-40-8
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration numbe
Sponsors
Heinrich-Heine-Universität Düsseldorf represented by the Coordinating Investigator
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: MDS, CMML or sAML (marrow blast count 5% and high-risk genetic features (eg. bad risk karyotype according to the IPSS-R / ELN classification or presence of unfavorable somatic mutations (e.g. TP53, RUNX1, IDH1, IDH2, KMT2A, DEK-NUP214 or RAS pathway mutations including NRAS, KRAS, PTPN11, CBL, NF1, RIT1 or KIT), falling into the “high” or “very high” risk category of the IPSS-R or IPSS M), or a marrow blast count >20% any time between diagnosis and inclusion. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 28 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
Exclusion criteria: previous cytotoxic therapy exceeding oral Hydroxyurea >60 days or >2 courses of treatment with Azacytidine or Decitabine alone or in combination with Venetoclax
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To find the MTD of Venetoclax when added to Fludarabin, Amsacrine and Ara-C + Treosulfan and evaluate , whether the addition of Venetoclax to sequential conditioning with Fludarabine + Amsacrine + Ara-C (FLAMSA) + Treosulfan for allogeneic blood stem cell transplantation in patients with high-risk MDS, CMML or sAML (FLAMSAClax) is safe;Secondary Objective: -To assess incidence, course und severity of aGvHD and cGvHD as well as incidence, course and severity of VOD and graft failure, time to hematopoietic reconstitution (ANC>500/µl, PLT>20000/µl and PLT>50000/µl) and time to transfusion independence -To analyse best response within the first 100 days (± 7) after transplantation (according to IWG-criteria for MDS and ELN-criteria for AML) as well as response rates at day +30 (± 3) , +60 (± 7) and +100 (± 7) after transplantation. In detail, time to complete donor chimerism in blood and marrow and disappearance of molecular markers of disease -To evaluate event-free survival, cumulative incidence of relapse and overall survival ;Primary end point(s): safety, defined as the maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater until day +30 (± 3) after transplantation ;Timepoint(s) of evaluation of this end point: 1. Review of Safety data until day +30 (± 3) (visit 3) by DMC after each dose cohort (dose finding phase I) and after every cohort of 10 patients treated in phase II 2. Review of Safety data by DMC at Interim analysis I (as soon as the phase I part of the study has been completed; review of all data of phase I subjects until day +30 (± 3) after transplantation) and II (as soon as all study subjects have passed day +100 (± 7) (visit 5) or have gone off study). 3. Annual Review of Safety Data by DMC, based on DSUR data 4. End of study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •safety, defined as the maximal organ toxicity to each organ system according to CTC criteria as well as the number of AEs of grade III or greater until day +100 (± 7) after transplantation •incidence, course und severity of aGvHD and cGvHD during the first 2 years after transplantation (see Appendix for definitions) •incidence, course and severity of VOD (see Appendix for definitions) •time (days from day 0) to hematopoietic reconstitution (ANC>500/µl, PLT>20000/µl and PLT>50000/µl) •Graft failure defined as no donor chimerism at day +30 (± 3) after transplantation •time (days from day 0) to transfusion independence •disappearance of molecular markers of disease (yes/no, time in days from day 0) •best response within the first 100 days (± 7) after transplantation (according to IWG-criteria for MDS and ELN-criteria for AML) •disease response and donor chimerism at day +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation (according to IWG-criteria for MDS and ELN-criteria for AML ) •time (days from day 0) to complete donor chimerism in blood and marrow •event-free survival (EFS, death, relapse and disease progression will be recorded as event ) •cumulative incidence of relapse (CIR, disease progression and relapse will be recorded as event ) •overall survival (OS, death will be recorded as event) ;Timepoint(s) of evaluation of this end point: 1. Review of Safety data until day +30 (± 3) (visit 3) by DMC after each dose cohort (dose finding phase I) and after every cohort of 10 patients treated in phase II 2. Review of Safety data by DMC at Interim analysis I (as soon as the phase I part of the study has been completed; review of all data of phase I subjects until day +30 (± 3) after transplantation) and II (as soon as all study subjects have passed day +100 (± 7) (visit 5) or have gone off study). 3. Annual Review of Safety Data by DMC, based on DSUR data 4. End of study | — |
Countries
Germany
Contacts
Public ContactCoordinating Investigator
University Hospital Düsseldorf, Dept. of Hematology, Oncology and Clinical Immunology
Outcome results
None listed