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

NCT ID: NCT05807932

Last Updated: 2024-05-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-26
• Study Completion Date: 2028-01-30

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Venetoclax

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).

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: DRUG

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

Amsacrine

Intervention Type: DRUG

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

Ara-C

Intervention Type: DRUG

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

Tacrolimus

Intervention Type: DRUG

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

Mycophenolate Mofetil

Intervention Type: DRUG

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

Interventions

Venetoclax

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

Intervention Type: DRUG

Amsacrine

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

Intervention Type: 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

Intervention Type: DRUG

Tacrolimus

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

Intervention Type: DRUG

Mycophenolate Mofetil

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

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Koordinierungszentrum für Klinische Studien - Duesseldorf

UNKNOWN

Sponsor Role: collaborator

Heinrich-Heine University, Duesseldorf

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guido Kobbe, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Coordinating Investigator

Locations

Universitätsklinikum Aachen - Med. Klinik IV

Aachen, North Rhine-Westphalia, Germany

Site Status: RECRUITING

Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie

Düsseldorf, North Rhine-Westphalia, Germany

Site Status: RECRUITING

Universitätsklinikum Köln Klinik I für Innere Medizin

Cologne, , Germany

Site Status: RECRUITING

Universitätsklinikum Frankfurt Medizinische Klinik II

Frankfurt, , Germany

Site Status: RECRUITING

Universitätsklinikum Jena - Klinik für Innere Medizin II

Jena, , Germany

Site Status: RECRUITING

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

München, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Guido Kobbe, Prof. Dr.

Role: CONTACT

kobbe@med.uni-duesseldorf.de

+492118116 ext. 826

Facility Contacts

Edgar Jost, Prof. Dr.

Role: primary

Guido Kobbe, Prof. Dr.

Role: primary

kobbe@med.uni-duesseldorf.de

Udo Holtick, PD Dr.

Role: primary

Gesine Bug, PD Dr.

Role: primary

Inken Hilgendorf, Prof. Dr.

Role: primary

Mareike Verbeek, Dr.

Role: primary

Other Identifiers

FLAMSAClax

Identifier Type: -

Identifier Source: org_study_id