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

NCT05807932 | Recruiting Phase 1 DMC

• 1 other identifier: FLAMSAClax
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 6

Brief 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)

Conditions

Myelodysplastic Syndromes; Secondary Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Keywords

MDS; sAML; CMML; allogeneic blood stem cell transplantation; Venetoclax

Outcome Measures

Primary Outcomes (1)

• 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

  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

  inclusion until day +100 (± 7) after transplantation

• Graft failure at day +30 (± 3) after transplantation

  transplantation until day +30 (± 3) after transplantation

• Incidence of aGvHD during the first 2 years after transplantation

  transplantation until 2 years after transplantation

• Course of aGvHD during the first 2 years after transplantation

  transplantation until 2 years after transplantation

• Severity of aGvHD during the first 2 years after transplantation

  transplantation until 2 years after transplantation

Study Arms (1)

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).

Drug: Venetoclax; Drug: Amsacrine; Drug: Ara-C; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

Interventions

Venetoclax DRUG

Study treatment consists of the conditioning therapy including 6 or 8 days of Venetoclax treatment.

Venetoclax

Amsacrine DRUG

Amsacrine is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation

Venetoclax

Ara-C DRUG

Ara-C is part of the conditioning therapy and is administered on day -10 to -7 before allogeneic blood stem cell transplantation

Venetoclax

Tacrolimus DRUG

Tacrolimus is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.

Venetoclax

Mycophenolate Mofetil DRUG

Mycophenolate Mofetil is used for prophylaxis of acute and chronic graft-versus-host-disease according to institutional standards.

Venetoclax

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• Heinrich-Heine University, Duesseldorf: lead
• Koordinierungszentrum für Klinische Studien - Duesseldorf: collaborator

Study Sites (6)

Universitätsklinikum Aachen - Med. Klinik IV

Aachen, North Rhine-Westphalia, 52074, Germany

RECRUITING

Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie

Düsseldorf, North Rhine-Westphalia, 40225, Germany

RECRUITING

Universitätsklinikum Köln Klinik I für Innere Medizin

Cologne, 50937, Germany

RECRUITING

Universitätsklinikum Frankfurt Medizinische Klinik II

Frankfurt, 60590, Germany

RECRUITING

Universitätsklinikum Jena - Klinik für Innere Medizin II

Jena, 07747, Germany

RECRUITING

Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III

München, 81675, Germany

RECRUITING

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Interventions

venetoclax; Amsacrine; Cytarabine; Tacrolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminoacridines; Acridines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Guido Kobbe, Prof. Dr.

  Coordinating Investigator

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Guido Kobbe, Prof. Dr.

CONTACT

+492118116; kobbe@med.uni-duesseldorf.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2023
• First Posted: April 11, 2023
• Study Start: June 26, 2023
• Primary Completion: January 31, 2026
• Study Completion (Estimated): January 30, 2028
• Last Updated: May 1, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (6)