Myelodysplastic SyndromesPhase 1/2NCT05807932
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
A Phase 1/2 study testing Venetoclax, Amsacrine and Ara-C in people with Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia, run by Heinrich-Heine University, Duesseldorf at 6 sites in Germany.
Trial summary
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) Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia
- What is being tested?
- Venetoclax, Amsacrine and Ara-C
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 6 sitesGermany
- Study dates
- 26 Jun 2023to 30 Apr 2029
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
6 sites in 1 country
Germany6 sites, 6 recruiting
- Recruiting
Universitätsklinikum Aachen - Med. Klinik IV
Aachen, North Rhine-Westphalia, 52074
Edgar Jost, Prof. Dr.
Edgar Jost, Prof. Dr.
- Recruiting
Universitätsklinikum Köln Klinik I für Innere Medizin
Cologne, 50937
Udo Holtick, PD Dr.
- Recruiting
Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie
Düsseldorf, North Rhine-Westphalia, 40225
Guido Kobbe, Prof. Dr., kobbe@med.uni-duesseldorf.de
Guido Kobbe, Prof. Dr.
- Recruiting
Universitätsklinikum Frankfurt Medizinische Klinik II
Frankfurt, 60590
Gesine Bug, PD Dr.
- Recruiting
Universitätsklinikum Jena - Klinik für Innere Medizin II
Jena, 07747
Inken Hilgendorf, Prof. Dr.
Inken Hilgendorf, Prof. Dr.
- Recruiting
Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III
München, 81675
Mareike Verbeek, Dr.
About this study
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
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)
- Conditions
- Myelodysplastic Syndromes, Secondary Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia
- Being tested
- Venetoclax, Amsacrine, Ara-C, Tacrolimus, Mycophenolate Mofetil
- Keywords
- MDS, sAML, CMML, allogeneic blood stem cell transplantation, Venetoclax
- Medical subject headings
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VenetoclaxDrug
Study treatment consists of the conditioning therapy including 6 or 8 days of Venetoclax treatment.
AmsacrineDrug
Amsacrine is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
Ara-CDrug
Ara-C is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation
TacrolimusDrug
Tacrolimus is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.
Mycophenolate Mofetil is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.
| Study group | Role | What they receive |
|---|---|---|
| Venetoclax | Experimental | Venetoclax treatment will be started orally once a day with food, one day before FLAMSA conditioning therapy and stopped the day before high-dose Treosulfan. The total duration of treatment with Venetoclax will be 6 days (day -11 to -6 before stem cell infusion). Patients with active disease at transplant will receive a 3-day ramp-up prephase of Ara-C (100mg total dose infused in 1h) with daily increasing doses of Venetoclax to prevent TLS during conditioning. Total treatment duration with Venetoclax in patients with active disease at transplant will be 8 days (day -13 to -6 before stem cell infusion). Receives: Drug: Venetoclax; Drug: Amsacrine; Drug: Ara-C; Drug: Tacrolimus; Drug: Mycophenolate Mofetil |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
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
Measured: inclusion until day 30 (± 3) after transplantation
Secondary outcomes (18)
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
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
Measured: inclusion until day +100 (± 7) after transplantation
Graft failure at day +30 (± 3) after transplantation
Number of patients with graft failure (no donor chimerism at day +30 (± 3) after transplantation)
Measured: transplantation until day +30 (± 3) after transplantation
Incidence of aGvHD during the first 2 years after transplantation
Incidence of aGvHD during the first 2 years after transplantation
Measured: transplantation until 2 years after transplantation
Course of aGvHD during the first 2 years after transplantation
Course of aGvHD during the first 2 years after transplantation (response/no response to steroids)
Measured: transplantation until 2 years after transplantation
Severity of aGvHD during the first 2 years after transplantation
Severity of aGvHD during the first 2 years after transplantation (according to Glucksberg criteria)
Measured: transplantation until 2 years after transplantation
Incidence of cGvHD during the first 2 years after transplantation
Incidence of cGvHD during the first 2 years after transplantation
Measured: transplantation until 2 years after transplantation
Course of cGvHD during the first 2 years after transplantation
Course of cGvHD during the first 2 years after transplantation (response/no response to steroids)
Measured: transplantation until 2 years after transplantation
Severity of cGvHD during the first 2 years after transplantation
Severity of cGvHD during the first 2 years after transplantation (according to NIH criteria)
Measured: transplantation until 2 years after transplantation
Incidence, course and severity of VOD
Incidence, course and severity of VOD (according to EBMT criteria)
Measured: transplantation until 2 years after transplantation
Time to hematopoietic reconstitution
Time (days from day 0) to hematopoietic reconstitution (ANC>500/µl, PLT>20000/µl and PLT>50000/µl)
Measured: From date of transplantation (day 0) until the date of first documented hematopoietic reconstitution, assessed up to day 100
Time to transfusion independence
Time (days from day 0) to transfusion independence
Measured: 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
Best disease response within the first 100 days (± 7) after transplantation (according to IWG-criteria for MDS and ELN-criteria for AML)
Measured: Transplantation to day 100 (± 7) after transplantation
Disease response and donor chimerism at day +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation
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)
Measured: Transplantation until days +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation
Time to complete donor chimerism in blood and marrow
Time (days from day 0) to complete donor chimerism in blood and marrow
Measured: From date of transplantation (day 0) until the date of first documented donor chimerism in blood and marrow, assessed up to day 100
Disappearance of molecular markers of disease
Disappearance of individual molecular markers of disease (time in days from day 0)
Measured: From date of transplantation (day 0) until the date of first documented disappearance of individual molecular marker, assessed through study completion, an average of 2 years
Event-free survival
Event-free survival (death,relapse and disease progression will be recorded as event)
Measured: inclusion until 2 years after transplantation
Cumulative incidence of relapse
Cumulative incidence of relapse (disease progression and relapse will be recorded as event)
Measured: inclusion until 2 years after transplantation
Overall survival
Overall survival (OS, death will be recorded as event)
Measured: inclusion until 2 years after transplantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2023
- Study start26 Jun 2023
- Primary completion30 Apr 2029 (estimated)
- Study completion30 Apr 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Myelodysplastic SyndromesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 38 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Heinrich-Heine University, Duesseldorf
- Sponsor type
- University, hospital or other
- Collaborators
- Koordinierungszentrum für Klinische Studien - Duesseldorf
- Responsible party
- Sponsor
- Investigators
- Guido Kobbe, Prof. Dr., Principal investigator, Coordinating Investigator
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05807932
- Sponsor's protocol ID
- FLAMSAClax
- Status last verified
- Sep 2026
- First submitted
- 3 Mar 2023
- Last updated
- 16 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No