Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (CLAG-M, 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. |
Drug: Cladribine
Given IV
Other Names:
Drug: Cytarabine
Given IV
Other Names:
Drug: Mitoxantrone
Given IV
Other Names:
Biological: Recombinant Granulocyte Colony-Stimulating Factor
Given subcutaneously
Other Names:
Drug: Venetoclax
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of adverse events [Up to 12 months]
- Maximum tolerated dose of venetoclax in combination with CLAG-M [Up to 12 months]
Secondary Outcome Measures
- Complete remission rate [After 2 cycles (each cycle is approximately 35 days)]
- 1-year survival rate [At 1 year]
- Rate of allogeneic hematopoietic cell transplant [At 1 year]
Eligibility Criteria
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
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Relapsed/refractory patients must require first or subsequent salvage therapy
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Patients with biphenotypic or mixed phenotype acute leukemia are eligible
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Age >= 18 years
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Aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 X upper limit of normal (ULN)
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Bilirubin =< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
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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
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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
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Eastern Cooperative Oncology Group (ECOG) =< 2
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Treatment-related mortality (TRM) score < 13.1
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Female subjects of childbearing potential must have negative results for pregnancy test
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Ability to understand and the willingness to sign a written informed consent document
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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:
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Acute promyelocytic leukemia or chronic myeloid leukemia in myeloid blast crisis
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Known active central nervous system (CNS) involvement with acute myeloid leukemia (AML)
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Concomitant illness associated with a likely survival of < 1 year
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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
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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
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Known hypersensitivity to any study drug
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Pregnancy or lactation because of the unknown risks of this combination
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Concurrent treatment with any other investigational agent
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Subject is known to be positive for human immunodeficiency virus (HIV)
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Treatment with any of the following within 7 days prior to the first dose of venetoclax
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Steroid therapy for anti-neoplastic intent
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fred Hutch/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- University of Washington
- AbbVie
Investigators
- Principal Investigator: Mary-Beth M. Percival, Fred Hutch/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- RG1121403
- NCI-2021-01379
- 10793