A Phase I/II Study of ASTX727, Venetoclax, and Gilteritinib for Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome With an Activating FLT3 Mutation
This phase I/II trial studies the best dose of gilteritinib given together with ASTX727 and venetoclax and the effect of ASTX727, venetoclax, and gilteritinib in treating patients with FLT3-mutated acute myeloid leukemia that is newly diagnosed, has come back (relapsed) or does not respond to treatment (refractory) or high-risk myelodysplastic syndrome. Chemotherapy drugs, such as ASTX727, 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. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ASTX727, venetoclax, and gilteritinib may help to control the disease.
• Diagnosis:
‣ Phase I cohort: Adults \>= 18 years with relapsed/refractory FLT3-mutated AML or myelodysplastic syndrome (MDS) that is intermediate-2 or high-risk by the International Prognostic Scoring System
⁃ Phase II cohort A: Adults \>= 18 years with newly diagnosed FLT3-mutated AML. Patients should meet the following criteria:
• Confirmed newly diagnosed AML with FLT3 mutation
∙ Ineligible for induction therapy defined as
‣ Either age \>= 75
⁃ Or 18-74 with at least one comorbidity (congestive heart failure \[CHF\] requiring therapy or ejection fraction \[EF\] =\< 50%, diffusion capacity of the lung for carbon monoxide \[DLCO\] =\< 65% or forced expiratory volume in 1 second \[FEV1\] =\< 65%, or Eastern Cooperative Oncology Group \[ECOG\] 2 or 3, or other significant co-morbidity precluding use of cytotoxic chemotherapy as approved by the principal investigator (PI)
⁃ Phase II cohort B: Adults \>= 18 years with relapsed/refractory FLT3-mutated AML or MDS that is intermediate-2 or high-risk by the International Prognostic Scoring System who have received 1 prior therapy
⁃ For all cohorts, patients with either FLT3-ITD or FLT3 D835 mutations will be eligible
• Performance status =\< 3 (Eastern Cooperative Oncology Group \[ECOG\] scale)
• Total serum bilirubin =\< 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 3 x ULN, unless due to the underlying leukemia approved by the PI
• Creatinine clearance \>= 30 mL/min
• Ability to swallow
• Signed informed consent
• Hydroxyurea or one dose of cytarabine up to 1000 mg is allowed to reduce the white blood cell (WBC) to less than 25 x 10\^9/L prior to initiation of study treatment