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

Primary Purpose

Acute Biphenotypic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia

Status
Suspended
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cladribine
Cytarabine
Mitoxantrone
Recombinant Granulocyte Colony-Stimulating Factor
Venetoclax
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Biphenotypic Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (CLAG-M, venetoclax)

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of adverse events
Maximum tolerated dose of venetoclax in combination with CLAG-M

Secondary Outcome Measures

Complete remission rate
1-year survival rate
Rate of allogeneic hematopoietic cell transplant

Full Information

First Posted
March 10, 2021
Last Updated
May 12, 2023
Sponsor
University of Washington
Collaborators
AbbVie
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1. Study Identification

Unique Protocol Identification Number
NCT04797767
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Suspended
Why Stopped
Pending protocol amendment
Study Start Date
February 4, 2022 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Washington
Collaborators
AbbVie

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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, Recurrent Myeloid Sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (CLAG-M, venetoclax)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cladribine
Other Intervention Name(s)
2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
.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-28453
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone
Other Intervention Name(s)
Dihydroxyanthracenedione, Mitozantrone
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Recombinant Granulocyte Colony-Stimulating Factor
Other Intervention Name(s)
Recombinant Colony-Stimulating Factor 3, rhG-CSF
Intervention Description
Given subcutaneously
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of adverse events
Time Frame
Up to 12 months
Title
Maximum tolerated dose of venetoclax in combination with CLAG-M
Time Frame
Up to 12 months
Secondary Outcome Measure Information:
Title
Complete remission rate
Time Frame
After 2 cycles (each cycle is approximately 35 days)
Title
1-year survival rate
Time Frame
At 1 year
Title
Rate of allogeneic hematopoietic cell transplant
Time Frame
At 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 as assessed by morphology or multiparameter flow cytometry at initial presentation). Patients with biphenotypic or mixed phenotype acute leukemia are eligible. Newly diagnosed patients presenting for trial entry must have adverse risk disease as per the European LeukemiaNet 2017 guidelines Relapsed/refractory patients presenting for trial entry must require first or subsequent salvage therapy and have detectable blasts in peripheral blood or >= 5% blasts in bone marrow, as assessed by morphology or multiparameter flow cytometry; or extramedullary myeloid sarcoma, per European LeukemiaNet 2017 guidelines. 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 and no clinical evidence of congestive heart failure 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. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must agree to use an effective method of birth control from the time of signing the consent form until at least 3 months after the last dose of study drug 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary-Beth M. Percival
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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