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.
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
Confirmed newly diagnosed AML with FLT3 mutation
Ineligible for induction therapy defined as
Either age >= 75
Prior therapies
Phase I cohort: No restriction based on prior therapies
Phase II cohort A: Patients with prior therapy for AML are not eligible. Prior therapy for antecedent hematologic disorder is allowed including prior hypomethylating agent (HMA) therapy for MDS. Prior hydroxyurea or cytarabine given for purposes of cytoreduction is also allowed. Prior all trans-retinoic acid given for presumed acute promyelocytic leukemia is also allowed
Phase II cohort B: Patients with >= 3 prior lines of therapy are not eligible. Stem cell transplantation, treatment given only for cytoreductive purposes (e.g. hydroxyurea), and growth factors do not count as lines of therapy for this purpose. Prior therapy with venetoclax and gilteritinib is allowed
Single group
Decitabine and Cedazuridine
DrugGiven PO
Gilteritinib
DrugGiven PO
Venetoclax
DrugGiven PO
Maximum tolerated dose (Phase I)
Overall response (OR) rate (Phase II)
Will estimate the OR for the combination treatment (defined as the proportion of patients achieving complete response (CR) or incomplete hematologic recovery (CRi) within 2 cycles of treatment), along with the 95% credible interval.
Complete response rate
Will also be estimated along with 95% credible interval.
To assess minimal residual disease negativity by flow cytometry
Will also be estimated along with 95% credible interval.
Relapse-free survival
Will be estimated using the method of Kaplan and Meier.
Overall survival
Will be estimated using the method of Kaplan and Meier.
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