ASTX727, Venetoclax, and Gilteritinib for the Treatment of Newly Diagnosed, Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Inclusion Criteria:

• Diagnosis:

• Phase I cohort: Adults >= 18 years with relapsed/refractory FLT3-mutated AML ormyelodysplastic syndrome (MDS) that is intermediate-2 or high-risk by theInternational 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%, diffusioncapacity of the lung for carbon monoxide [DLCO] =< 65% or forcedexpiratory volume in 1 second [FEV1] =< 65%, or Eastern CooperativeOncology Group [ECOG] 2 or 3, or other significant co-morbidityprecluding use of cytotoxic chemotherapy as approved by the principalinvestigator (PI)

• Phase II cohort B: Adults >= 18 years with relapsed/refractory FLT3-mutated AMLor MDS that is intermediate-2 or high-risk by the International PrognosticScoring System who have received 1 prior therapy

• For all cohorts, patients with either FLT3-ITD or FLT3 D835 mutations will beeligible

• Performance status =< 3 (Eastern Cooperative Oncology Group [ECOG] scale)

• Total serum bilirubin =< 2.5 x upper limit of normal (ULN), unless due to Gilbert'ssyndrome, 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 whiteblood cell (WBC) to less than 25 x 10^9/L prior to initiation of study treatment

Exclusion Criteria:

• Prior therapies

• Phase I cohort: No restriction based on prior therapies

• Phase II cohort A: Patients with prior therapy for AML are not eligible. Priortherapy for antecedent hematologic disorder is allowed including priorhypomethylating agent (HMA) therapy for MDS. Prior hydroxyurea or cytarabinegiven for purposes of cytoreduction is also allowed. Prior all trans-retinoicacid 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 forthis purpose. Prior therapy with venetoclax and gilteritinib is allowed

• Patients suitable for and willing to receive intensive induction chemotherapy (forPhase II cohort A only)

• Congenital long QT syndrome or corrected QT (QTc) > 450 msec. Repeatelectrocardiograms (EKGs) after correction of electrolytes or discontinuation of QTprolonging medications are allowed to meet entry criteria

• Active serious infection not controlled by oral or intravenous antibiotics (e.g.persistent fever or lack of improvement despite antimicrobial treatment)

• Active grade III-V cardiac failure as defined by the New York Heart AssociationCriteria

• Active central nervous system leukemia

• Known hepatitis B surface antigen seropositive or known or suspected activehepatitis C infection

• Note: Patients who have isolated positive hepatitis B core antibody (i.e., inthe setting of negative hepatitis B surface antigen and negative hepatitis Bsurface antibody) must have an undetectable hepatitis B viral load. Patientswho have positive hepatitis C antibody may be included if they have anundetectable hepatitis C viral load

• Patients with a prior or concurrent malignancy whose natural history or treatment isnot anticipated to interfere with the safety or efficacy assessment of theinvestigational regimen may be included only after discussion with the PI

• Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of studyenrollment. Agents include but are not limited to: carbamazepine, phenytoin,rifampin, and St. John's wart

• Treatment with any investigational antileukemic agents or chemotherapy agents in thelast 7 days before study entry, unless full recovery from side effects has occurredor patient has rapidly progressive disease judged to be life-threatening by theinvestigator. Prior recent treatment with corticosteroids, hydroxyurea and/orcytarabine (given for cytoreduction) permitted. Use of hydroxyurea or one dosecytarabine to reduce WBC below 25 prior to initiation of study treatment isrecommended

• Pregnant women will not be eligible; women of childbearing potential should have anegative pregnancy test prior to entering on the study and be willing to useeffective methods of contraception throughout the study period and for at least 6months after the last dose of study drugs. Women do not have childbearing potentialif they have had a hysterectomy or are postmenopausal without menses for 12 months.In addition, men enrolled on this study should understand the risks to any sexualpartner of childbearing potential and should practice an effective method of birthcontrol throughout the study period and for at least 4 months after the last dose ofstudy drugs. Lactating women (or those planning to breastfeed) should not breastfeedduring treatment of gilteritinib and for at least 2 months after the last dose ofgilteritinib

• Medical, psychiatric, cognitive or other conditions that compromise the patient'sability to understand the patient information, to give informed consent, to complywith the study protocol or to complete the study