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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05807932
• Other study ID #: FLAMSAClax
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 26, 2023
• Est. completion date: January 30, 2028

Study information

• Verified date: April 2024
• Source: Heinrich-Heine University, Duesseldorf
• Contact: Guido Kobbe, Prof. Dr.
• Phone: +492118116
• Email: kobbe[@]med.uni-duesseldorf.de
• Is FDA regulated: No
• Study type: Interventional

Clinical 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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 38
• Est. completion date: January 30, 2028
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Secondary Acute Myeloid Leukemia

Intervention

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

Locations

Country	Name	City	State
Germany	Universitätsklinikum Aachen - Med. Klinik IV	Aachen	NRW
Germany	Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie	Düsseldorf	NRW
Germany	Universitätsklinikum Frankfurt Medizinische Klinik II	Frankfurt
Germany	Universitätsklinikum Jena - Klinik für Innere Medizin II	Jena
Germany	Universitätsklinikum Köln Klinik I für Innere Medizin	Köln
Germany	Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III	München

Sponsors (2)

Lead Sponsor	Collaborator
Heinrich-Heine University, Duesseldorf	Koordinierungszentrum für Klinische Studien - Duesseldorf

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	inclusion until day +100 (± 7) after transplantation
Secondary	Graft failure at day +30 (± 3) after transplantation	Number of patients with graft failure (no donor chimerism at day +30 (± 3) after transplantation)	transplantation until day +30 (± 3) after transplantation
Secondary	Incidence of aGvHD during the first 2 years after transplantation	Incidence of aGvHD during the first 2 years after transplantation	transplantation until 2 years after transplantation
Secondary	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)	transplantation until 2 years after transplantation
Secondary	Severity of aGvHD during the first 2 years after transplantation	Severity of aGvHD during the first 2 years after transplantation (according to Glucksberg criteria)	transplantation until 2 years after transplantation
Secondary	Incidence of cGvHD during the first 2 years after transplantation	Incidence of cGvHD during the first 2 years after transplantation	transplantation until 2 years after transplantation
Secondary	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)	transplantation until 2 years after transplantation
Secondary	Severity of cGvHD during the first 2 years after transplantation	Severity of cGvHD during the first 2 years after transplantation (according to NIH criteria)	transplantation until 2 years after transplantation
Secondary	Incidence, course and severity of VOD	Incidence, course and severity of VOD (according to EBMT criteria)	transplantation until 2 years after transplantation
Secondary	Time to hematopoietic reconstitution	Time (days from day 0) to hematopoietic reconstitution (ANC>500/µl, PLT>20000/µl and PLT>50000/µl)	From date of transplantation (day 0) until the date of first documented hematopoietic reconstitution, assessed up to day 100
Secondary	Time to transfusion independence	Time (days from day 0) to transfusion independence	From date of transplantation (day 0) until the date of first documented transfusion independence, assessed up to day 100
Secondary	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)	Transplantation to day 100 (± 7) after transplantation
Secondary	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)	Transplantation until days +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation
Secondary	Time to complete donor chimerism in blood and marrow	Time (days from day 0) to complete donor chimerism in blood and marrow	From date of transplantation (day 0) until the date of first documented donor chimerism in blood and marrow, assessed up to day 100
Secondary	Disappearance of molecular markers of disease	Disappearance of individual molecular markers of disease (time in days from day 0)	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
Secondary	Event-free survival	Event-free survival (death,relapse and disease progression will be recorded as event)	inclusion until 2 years after transplantation
Secondary	Cumulative incidence of relapse	Cumulative incidence of relapse (disease progression and relapse will be recorded as event)	inclusion until 2 years after transplantation
Secondary	Overall survival	Overall survival (OS, death will be recorded as event)	inclusion until 2 years after transplantation