Clinical trial NCT05807932: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndromes
Secondary Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Keywords: MDS
sAML
CMML
allogeneic blood stem cell transplantation
Venetoclax
Lead sponsor: Heinrich-Heine University, Duesseldorf
Sponsor class: OTHER
Collaborators: name: Koordinierungszentrum für Klinische Studien - Duesseldorf
First posted: 2023-04-11
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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)


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

Primary outcomes:
measure: 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
timeFrame: inclusion until day 30 (± 3) after transplantation
Secondary outcomes:
measure: 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
timeFrame: inclusion until day +100 (± 7) after transplantation
measure: Graft failure at day +30 (± 3) after transplantation
timeFrame: transplantation until day +30 (± 3) after transplantation
measure: Incidence of aGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Course of aGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Severity of aGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Incidence of cGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Course of cGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Severity of cGvHD during the first 2 years after transplantation
timeFrame: transplantation until 2 years after transplantation
measure: Incidence, course and severity of VOD
timeFrame: transplantation until 2 years after transplantation
measure: Time to hematopoietic reconstitution
timeFrame: From date of transplantation (day 0) until the date of first documented hematopoietic reconstitution, assessed up to day 100
measure: Time to transfusion independence
timeFrame: From date of transplantation (day 0) until the date of first documented transfusion independence, assessed up to day 100
measure: Best disease response within the first 100 days (± 7) after transplantation
timeFrame: Transplantation to day 100 (± 7) after transplantation
measure: Disease response and donor chimerism at day +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation
timeFrame: Transplantation until days +30 (± 3), +60 (± 7) and +100 (± 7) after transplantation
measure: Time to complete donor chimerism in blood and marrow
timeFrame: From date of transplantation (day 0) until the date of first documented donor chimerism in blood and marrow, assessed up to day 100
measure: Disappearance of molecular markers of disease
timeFrame: 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
measure: Event-free survival
timeFrame: inclusion until 2 years after transplantation
measure: Cumulative incidence of relapse
timeFrame: inclusion until 2 years after transplantation
measure: Overall survival
timeFrame: inclusion until 2 years after transplantation
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen - Med. Klinik IV
state: NRW
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie
state: NRW
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt Medizinische Klinik II
city: Jena
country: Germany
facility: Universitätsklinikum Jena - Klinik für Innere Medizin II
city: Köln
country: Germany
facility: Universitätsklinikum Köln Klinik I für Innere Medizin
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III
Study officials:
affiliation: Coordinating Investigator
name: Guido Kobbe, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: