Phase-I/II Trial to Assess the Safety and Efficacy of Venetoclax in Addition to Sequential Conditioning With Fludarabine / Amsacrine / Ara-C (FLAMSA) + Treosulfan for Allogeneic Blood Stem Cell Transplantation in Patients With MDS, CMML or sAML (FLAMSAClax
This trial aims to find the MTD of Venetoclax when added to Fludarabin, Amsacrine and Ara-C + Treosulfan and to evaluate whether the addition of Venetoclax to sequential conditioning with FLAMSA + Treosulfan is safe for allogeneic blood stem cell transplantation in patients with high-risk MDS, CMML or sAML (FLAMSAClax)
• Subjects must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC), prior to the initiation of any study-specific procedures
• MDS, CMML or sAML according to WHO classification (revised version 2016) with a marrow blast count \>5% and/or high-risk genetic features (e.g. 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) any time between diagnosis and inclusion
• Untreated except for oral Hydroxyurea or a maximum of 2 courses of treatment with Azacytidine or Decitabine alone or in combination with Venetoclax
• Identification of a well matched (10 out of 10, A, B, C, DR, DQ) donor either related or unrelated
• Age ≥18
• HCT-CI ≤ 3 (except former treatment of a solid tumor)
• ECOG performance status ≤ 2 at study entry
• no active, uncontrolled infection at inclusion
• able to adhere to the study visit schedule and other protocol requirements
• Female of childbearing potential (FCBP) must:
‣ Understand that based on embryo-foetal toxicity studies in animals venetoclax may harm the foetus when administered to pregnant woman
⁃ Agree to have a medically supervised pregnancy test at Screening and within 72 hours prior treatment start
⁃ Avoid becoming pregnant while receiving Venetoclax
⁃ Use effective contraception during treatment with Venetoclax and for at least 1 months after the last dose,
⁃ Understand that is currently unknown whether venetoclax may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method
⁃ Notify her study doctor immediately if there is a risk of pregnancy
• Males must:
‣ agree to use condoms, even if the male subject has undergone a successful vasectomy, from Study Day 1 through at least 30 days after the last dose of study drug.
⁃ Agree to notify the investigator immediately, if pregnancy or a positive pregnancy test occurs in his partner during study participation