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
Conditions
Brief summary
This phase I/II trial finds the best dose, side effects and how well giving 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 subcutaneously (SC) on days 0-5 (if peripheral white blood cell count is less than 20,000/uL), cladribine intravenously (IV) on days 1-5, cytarabine IV on days 1-5, and mitoxantrone IV 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. Patients undergo bone marrow biopsy and/or aspiration, and blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for 12 months.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
DRUGCladribine
Given IV
DRUGCytarabine
Given IV
DRUGMitoxantrone
Given IV
Given subcutaneously
DRUGVenetoclax
Given PO
PROCEDUREBone Marrow Aspiration
Undergo bone marrow aspiration
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
Sponsors
AbbVie
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * PHASE I: * 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. * These patients are only allowed in the phase 1 portion of the trial * PHASE II: Newly diagnosed patients presenting for trial entry must have adverse risk disease as per the European LeukemiaNet 2022 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of adverse events (Phase I) | Up to 12 months |
| Maximum tolerated dose of venetoclax in combination with CLAG-M (Phase I) | Up to 12 months |
| Event free survival (Phase II) | At 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Complete remission rate | After 2 cycles (each cycle is approximately 35 days) |
| Overall survival | At 1 year |
| Rate of minimal residual disease negativity | Up to 1 year |
| Rate of allogeneic hematopoietic cell transplant | At 1 year |
Countries
United States
Contacts
Primary ContactKim Quach
Backup ContactMary-Beth M. Percival
Outcome results
None listed