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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Relapsed Mixed Phenotype Acute Leukemia, Acute Biphenotypic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, Myeloid Neoplasm, Relapsed Acute Biphenotypic Leukemia, Relapsed Acute Myeloid Leukemia, Relapsed Myeloid Neoplasm, Refractory Acute Biphenotypic Leukemia, Refractory Acute Myeloid Leukemia, Refractory Mixed Phenotype Acute Leukemia, Refractory Myeloid Neoplasm, Recurrent Myeloid Sarcoma

Intervention / Treatment
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* Drug: Cladribine
* Drug: Cytarabine
* Drug: Mitoxantrone
* Biological: Recombinant Granulocyte Colony-Stimulating Factor
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 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) Subjects who cannot discontinue concomitant CYP3A inhibitors, except for voriconazole, prior to cycle 1 day 1 (C1D1) 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CLAG-M, venetoclax)<br>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<br>* Given IV<br>* Other names: RWJ-26251;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Mitoxantrone<br>* Given IV<br>* Other names: Mitozantrone;Biological: Recombinant Granulocyte Colony-Stimulating Factor<br>* Given subcutaneously<br>* Other names: rhG-CSF;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |