Clinical Trials /

Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms

NCT04797767

Description:

This phase I trial finds the best dose and side effects of venetoclax in combination with cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in treating patients with acute myeloid leukemia and high-grade myeloid neoplasms. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cladribine, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with CLAG-M may kill more cancer cells.

Related Conditions:
  • Acute Biphenotypic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myeloid Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
  • Official Title: A Phase 1 Single-Center Trial Combining Venetoclax With G-CSF, Cladribine, Cytarabine, and Mitoxantrone (CLAG-M) for Patients With AML and High-Grade Myeloid Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: RG1121403
  • SECONDARY ID: NCI-2021-01379
  • NCT ID: NCT04797767

Conditions

  • Acute Biphenotypic Leukemia
  • Acute Myeloid Leukemia
  • Mixed Phenotype Acute Leukemia
  • Myeloid Neoplasm
  • Relapsed Acute Biphenotypic Leukemia
  • Relapsed Acute Myeloid Leukemia
  • Relapsed Mixed Phenotype Acute Leukemia
  • Relapsed Myeloid Neoplasm
  • Refractory Acute Biphenotypic Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Mixed Phenotype Acute Leukemia
  • Refractory Myeloid Neoplasm

Interventions

DrugSynonymsArms
Cladribine2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251Treatment (CLAG-M, venetoclax)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (CLAG-M, venetoclax)
MitoxantroneDihydroxyanthracenedione, MitozantroneTreatment (CLAG-M, venetoclax)
Recombinant Granulocyte Colony-Stimulating FactorRecombinant Colony-Stimulating Factor 3, rhG-CSFTreatment (CLAG-M, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (CLAG-M, venetoclax)

Purpose

This phase I trial finds the best dose and side effects of venetoclax in combination with cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in treating patients with acute myeloid leukemia and high-grade myeloid neoplasms. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cladribine, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax with CLAG-M may kill more cancer cells.

Detailed Description

      OUTLINE:

      This is a dose-escalation study of venetoclax.

      Patients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if
      peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine
      on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days
      1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone,
      and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (CLAG-M, venetoclax)ExperimentalPatients will receive induction with granulocyte colony-stimulating factor on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine on days 1-5, cytarabine on 1-5, and mitoxantrone on days 1-3. Patients also receive venetoclax orally (PO) on days 1-14. Treatment repeats every 28-35 days for up to 2 induction cycles including mitoxantrone, and up to 4 consolidation cycles without mitoxantrone in the absence of disease progression or unacceptable toxicity.
  • Cladribine
  • Cytarabine
  • Mitoxantrone
  • Recombinant Granulocyte Colony-Stimulating Factor
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Acute myeloid leukemia (per the World Health Organization [WHO] 2016 classification)
             or high-grade myeloid neoplasm (>= 10% myeloid blasts in peripheral blood or marrow)

               -  Newly diagnosed patients must have adverse risk disease as per the European
                  LeukemiaNet 2017 guidelines

               -  Relapsed/refractory patients must require first or subsequent salvage therapy

               -  Patients with biphenotypic or mixed phenotype acute leukemia are eligible

          -  Age >= 18 years

          -  Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 X upper limit of
             normal (ULN)

          -  Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
             non-hepatic origin)

          -  Subject must have adequate renal function as demonstrated by a creatinine clearance >=
             30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine
             collection

          -  Left ventricular ejection fraction (LVEF) >= 45%, assessed by multigated acquisition
             (MUGA) or echocardiogram (ECHO) within 3 months prior to study day 0 or after most
             recent anthracycline administration if appropriate

          -  Eastern Cooperative Oncology Group (ECOG) =< 2

          -  Treatment-related mortality (TRM) score < 13.1

          -  Female subjects of childbearing potential must have negative results for pregnancy
             test

          -  Ability to understand and the willingness to sign a written informed consent document

          -  White blood cell count in peripheral blood must be < 25,000/ul prior to initiation of
             study therapy (CLAG-M plus venetoclax). Cytoreduction with hydroxyurea and/or
             cytarabine (e.g., 500 mg/m^2 per dose) is allowed to decrease the risk of tumor lysis
             syndrome

        Exclusion Criteria:

          -  Acute promyelocytic leukemia or chronic myeloid leukemia in myeloid blast crisis

          -  Known active central nervous system (CNS) involvement with acute myeloid leukemia
             (AML)

          -  Concomitant illness associated with a likely survival of < 1 year

          -  Active systemic infection, unless disease is under treatment with antimicrobials and
             considered controlled or stable; patients with fever thought to be likely secondary to
             leukemia are eligible. Patients with chronic hepatitis B virus (HBV) or hepatitis C
             (HCV) requiring treatment would be excluded. Note: subjects with serologic evidence of
             prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs
             antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive
             anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate

          -  Active or clinically significant (or symptomatic) cardiac disease, including active
             coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other
             than beta blockers or digoxin within the last 3 months, unstable angina (anginal
             symptoms at rest), new-onset angina within 3 months before randomization, or
             myocardial infarction within 6 months before study day 0

          -  Known hypersensitivity to any study drug

          -  Pregnancy or lactation because of the unknown risks of this combination

          -  Concurrent treatment with any other investigational agent

          -  Subject is known to be positive for human immunodeficiency virus (HIV)

          -  Treatment with any of the following within 7 days prior to the first dose of
             venetoclax

               -  Steroid therapy for anti-neoplastic intent

          -  Administration or consumption of any of the following within 3 days prior to the first
             dose of venetoclax:

               -  Grapefruit or grapefruit products

               -  Seville oranges (including marmalade containing Seville oranges)

               -  Star fruit
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Complete remission rate
Time Frame:After 2 cycles (each cycle is approximately 35 days)
Safety Issue:
Description:
Measure:1-year survival rate
Time Frame:At 1 year
Safety Issue:
Description:
Measure:Rate of allogeneic hematopoietic cell transplant
Time Frame:At 1 year
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Washington

Last Updated

April 22, 2021