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

Official title

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

Overview

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)

Interventions

• Drug Venetoclax
  Study treatment consists of the conditioning therapy including 6 or 8 days of Venetoclax treatment.
• Drug Amsacrine
  Amsacrine is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
• Drug Ara-C
  Ara-C is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
• Drug Tacrolimus
  Tacrolimus is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.
• Drug Mycophenolate Mofetil
  Mycophenolate Mofetil is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.

Primary outcome measures

• The primary target variable is 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 within the first 30 days (± 3) after transplantation [Time frame: inclusion until day 30 (± 3) after transplantation]

Secondary outcome measures (12)

• 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 [Time frame: inclusion until day +100 (± 7) after transplantation]
• Graft failure at day +30 (± 3) after transplantation [Time frame: transplantation until day +30 (± 3) after transplantation]
• Incidence of aGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Course of aGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Severity of aGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Incidence of cGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Course of cGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Severity of cGvHD during the first 2 years after transplantation [Time frame: transplantation until 2 years after transplantation]
• Incidence, course and severity of VOD [Time frame: transplantation until 2 years after transplantation]
• Time to hematopoietic reconstitution [Time frame: From date of transplantation (day 0) until the date of first documented hematopoietic reconstitution, assessed up to day 100]
• Time to transfusion independence [Time frame: From date of transplantation (day 0) until the date of first documented transfusion independence, assessed up to day 100]
• Best disease response within the first 100 days (± 7) after transplantation [Time frame: Transplantation to day 100 (± 7) after transplantation]

Eligibility criteria

Inclusion criteria

• 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

Exclusion criteria

• sAML with known FLT3 mutation (ITD or TKD)
• Marrow blast count >30% at the time of screening
• Peripheral white blood count >20,000 per microliter despite treatment with Hydroxyurea
• previous cytotoxic therapy exceeding oral Hydroxyurea or >2 courses of treatment with Azacytidine, Decitabine or low dose Ara-C alone or in combination with Venetoclax
• previous allogeneic blood stem cell transplantation
• symptomatic CNS-involvement with MDS; CMML or sAML
• any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• pregnant or lactating females
• Refusal to use safe contraceptive methods during the study period
• Cardiac history of CHF (>NYHA 2) requiring treatment or Ejection Fraction < 40% or chronic stable angina
• Forced expiratory volume in 1 second (FEV1) <50% of expected corrected for hemoglobin and/or volume
• Diffusing capacity of the lungs for carbon monoxide (DLCO) <50% of expected corrected for hemoglobin and/or volume
• any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study:

• Impaired renal function (GFR < 45 ml/min)
• Impaired hepatic function, as follows Aspartate aminotransferase (AST) ≥3 x ULN or Alanine aminotransferase (ALT) ≥3 x ULN or Total bilirubin ≥1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) or Alkaline Phosphatase ≥3 x ULN
• known hypersensitivity to Venetoclax, Fludarabine, Amsacrine, Ara-C or Treosulfan
• concurrent use of other anti-cancer agents or treatments except Hydroxyurea and a maximum of 2 courses of Azacytidine or Decitabine
• positive for HIV or replicating infectious hepatitis, type A, B, C or E
• prior history of malignancy other than MDS, CMML, sAML (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 2 years
• participation in another study with ongoing use of unlicensed investigational product from 28 days or <5 half-lifes of the investigational product before study enrollment
• No planned or executed/given treatment with any of the following within 7 days prior to the first dose of study drug (or ramp-up prophase):

• Steroid therapy for anti-neoplastic intent
• moderate or strong cytochrome P450 3A (CYP3A) inhibitors
• moderate or strong CYP3A inducers
• Refusal to avoid consumption of any of the following within 3 days prior to the first dose of study drug: grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), star fruit.
• Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
• Persons held in an institution by legal or official order

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 6 centers

• Universitätsklinikum Aachen - Med. Klinik IV — Aachen
• Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunolo — Düsseldorf
• Universitätsklinikum Köln Klinik I für Innere Medizin — Cologne
• Universitätsklinikum Frankfurt Medizinische Klinik II — Frankfurt
• Universitätsklinikum Jena - Klinik für Innere Medizin II — Jena
• Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III — München

Identifiers

NCT: NCT05807932 · FLAMSAClax

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗