A Study of Gilteritinib in Combination With Ivosidenib or Enasidenib in People With Acute Myeloid Leukemia (AML)

Inclusion Criteria:

• Adult patient is ≥18 years of age at the time of signing the informed consent form (ICF)

• Patient is willing and able to adhere to the study visit schedule and other protocolrequirements.

• Patient has a confirmed diagnosis of relapsed AML as per World Health Organization (2016) guidelines. Patients in morphologic remission with the reappearance of MRDare also eligible to participate OR the patient has refractory AML as defined below:

1. For patients who received intensive induction chemotherapy they must havepersistent AML (defined as overt disease with over 5% myeloblasts) after atleast one cycle of intensive induction OR

2. For patients treated with low intensity therapy, the patient must be refractoryto treatment with a single agent hypomethylating agent (HMA) or low dosecytarabine (LDAC) (at least two cycles) or an HMA/LDAC in combination withvenetoclax (at least one cycle) or another standard of care therapy (e.g.gemtuzumab ozogamicin, glasdegib/LDAC).

• Patient has relapsed or refractory AML with dually mutant IDH2/FLT3, IDH1/FLT3 (ITDor TKD) , or other FLT3 mutation sensitive to gilteritinib. a. A Patient receiving enasidenib or ivosidenib as a single agent who acquires aFLT3 mutation during treatment or a patient on single agent gilteritinib whoacquires an IDH2 or IDH1 mutation during treatment is eligible to participate inthis study

• Patient has documentation of FLT3 and IDH1 or IDH2 mutation in bone marrow or bloodat time of relapsed/refractory status confirmed by next-generation sequencing (NGS)and/or polymerase chain reaction (PCR) or fragment length analysis within theprevious 30 days by a local CLIA approved test.

• Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

• Patient should have adequate renal function, defined as creatine clearance ≥30mL/mincalculated using the Cockcroft-Gault equation or a serum creatinine less than 2.0.

• Patient should have adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x the upper limit of normal (ULN) andserum direct bilirubin ≤ 2.0 x ULN. Patient with leukemic organ involvement asassessed by the study investigator, must have a serum direct bilirubin ≤ 5.0 x ULN.

• Patient who has previously had an autologous or allogeneic stem cell transplant forAML is allowed on study.

• Female patient of childbearing potential must have had a negative pregnancy testwithin 7 days of initiation of dosing and must agree to use two acceptable methodsof birth control while on treatment. A woman must agree to remain on a highlyeffective method throughout the study and for at least 6 months after the last doseof study drug. A female is considered fertile following menarche and until becomingpostmenopausal unless permanently sterile.

• Male participants with female partners of childbearing potential are eligible forparticipation in the study if they agree to the following during treatment and untilthe end of relevant systemic exposure defined as 6 months after final drugadministration.

Exclusion Criteria:

• Patient has a diagnosis of acute promyelocytic leukemia (APL).

• Patient on any other investigational anti-cancer agents.

• Patient has active uncontrolled systemic fungal, bacterial, or viral infection.

• Patient has presence of any other condition that may increase the risk associatedwith study participation, and in the opinion of the investigator, would make thepatient inappropriate for entry into the study.

• Patient has immediate life-threatening, severe complications of leukemia such asuncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminatedintravascular coagulation.

• Patient has significant active cardiac disease within 6 months prior to the start ofstudy treatment, including New York Heart Association (NYHA) class III or IVcongestive heart failure; acute coronary syndrome (ACS); and/or ischemic stroke.

• Patient has left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO)or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start ofstudy treatment.

• Patient is known to have dysphagia, short-gut syndrome, gastroparesis, or otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered orally.

• Patient has a medical history of progressive multifocal leukoencephalopathy.

• Patient has QTc interval (i.e., Fridericia's correction [QTcF]) ≥ 450 ms (mean oftriplicate ECG) or other factors that increase the risk of QT prolongation orventricular arrhythmic events (e.g. family history of long QT interval syndrome).Patients with a QTcF over 450 ms due to a bundle branch block or a pacemaker mayparticipate in the study with approval of the study principal investigator.

• Patient has active graft-versus-host disease. However patients with isolated skinGVH controlled with topical steroids are eligible to participate

• Female patient who is pregnant or lactating.