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

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)

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Secondary Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Venetoclax; Drug: Amsacrine; Drug: Ara-C; Drug: Tacrolimus; Drug: Mycophenolate Mofetil

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Guido Kobbe, Prof. Dr.; Phone Number: 826 +492118116; Email: kobbe@med.uni-duesseldorf.de

Study Locations

• Germany
  • Frankfurt, Germany, 60590
    • Not yet recruiting
    • Universitätsklinikum Frankfurt Medizinische Klinik II
    • Contact: Gesine Bug, PD Dr.
  • Jena, Germany, 07747
    • Recruiting
    • Universitätsklinikum Jena - Klinik für Innere Medizin II
    • Contact: Inken Hilgendorf, Prof. Dr.
    • Principal Investigator: Inken Hilgendorf, Prof. Dr.
  • Köln, Germany, 50937
    • Recruiting
    • Universitatsklinikum Koln Klinik I fur Innere Medizin
    • Contact: Udo Holtick, PD Dr.
  • München, Germany, 81675
    • Recruiting
    • Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III
    • Contact: Mareike Verbeek, Dr.
  • NRW
    • Aachen, NRW, Germany, 52074
      • Recruiting
      • Universitätsklinikum Aachen - Med. Klinik IV
      • Principal Investigator: Edgar Jost, Prof. Dr.
      • Contact: Edgar Jost, Prof. Dr.
    • Düsseldorf, NRW, Germany, 40225
      • Recruiting
      • Universitätsklinikum Düsseldorf - Klinik für Hämatologie, Onkologie und Klinische Immunologie
      • Contact: Guido Kobbe, Prof. Dr.; Email: kobbe@med.uni-duesseldorf.de
      • Principal Investigator: Guido Kobbe, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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).

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
Incidence, course and severity of VOD	Incidence, course and severity of VOD (according to EBMT criteria)	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)	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	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)	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)	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	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)	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)	inclusion until 2 years after transplantation
Cumulative incidence of relapse	Cumulative incidence of relapse (disease progression and relapse will be recorded as event)	inclusion until 2 years after transplantation
Overall survival	Overall survival (OS, death will be recorded as event)	inclusion until 2 years after transplantation

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborators: Koordinierungszentrum für Klinische Studien - Duesseldorf
• Investigators: Principal Investigator: Guido Kobbe, Prof. Dr., Coordinating Investigator

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2023
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): January 30, 2028

Study Registration Dates

• First Submitted: March 3, 2023
• First Submitted That Met QC Criteria: March 29, 2023
• First Posted (Actual): April 11, 2023

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: MDS; Venetoclax; CMML; allogeneic blood stem cell transplantation; sAML
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Chronic Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Venetoclax; Tacrolimus; Mycophenolic Acid; Amsacrine
• Other Study ID Numbers: FLAMSAClax

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No