SNDX-5613 and Gilteritinib for the Treatment of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia and Concurrent MLL-Rearrangement or NPM1 Mutation

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study

• Age ≥ 18 years at the date of signing the informed consent form (ICF)

• Morphologically confirmed diagnosis of the following based on 2022 World HealthOrganization (WHO) classification:

• Relapsed or Refractory Acute Myeloid Leukemia with the following:

• Refractory disease classified as having received 2 cycles of intensiveinduction or 2 cycles of hypomethylating agent (HMA) + Venetoclax withpersistent disease of ≥ 5% blasts in the bone marrow and/or reappearanceof peripheral blasts

• FLT-3 mutated disease of the ITD or TKD subtype, AND

• NPM1 mutation, MLL gene rearrangement and any other mutation that has provenHOXA-MEIS1 overexpression (NUP98, UBTF-TD, MLL-PTD and any others that havesupporting literature)

• Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis for at least 24 hours prior toenrollment and while on SNDX-5613 treatment. Patients must not be receiving anyother strong CYP3A4 inhibitors/inducers

• Not suitable for immediate myeloablative/intensive chemotherapy based oninvestigator assessment of age, comorbidities, local guidelines, institutionalpractice (any or all of these)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upperlimit of normal (ULN)

• Total bilirubin ≤ 1.5 × ULN (except in the setting of isolated Gilbert syndrome)

• Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73m^2 (estimation based onModification of Diet in Renal Disease (MDRD) formula, by local laboratory)

• Adequate cardiac function defined as ejection fraction (EF) of ≥50% byechocardiogram or multigated acquisition (MUGA) scan

• Patient can communicate with the investigator and has the ability to comply with therequirements of the study procedures

• Participants of childbearing potential must agree to have a negative serum pregnancytest at screening and a negative serum or urine pregnancy test on the first day ofstudy treatment

• Participants capable of impregnating others who are having intercourse with peopleof childbearing potential must agree to abstain from intercourse or have theirpartner use 2 forms of contraception from the screening visit until 90 days afterthe last dose of study treatment. They must also refrain from sperm donation fromthe screening visit until 90 days following the last dose of study treatment

• Must be able to swallow the study medications

• Any prior treatment-related toxicities resolved to ≤ grade 1 prior to enrollment,with the exception of ≤ grade 2 neuropathy or alopecia

• Patients are not currently receiving the following therapies or have discontinuedtherapy based on the time periods below:

• Radiation Therapy: At least 60 days from prior total body irradiation (TBI),craniospinal radiation and/or ≥ 50% radiation of the pelvis, or at least 14days from local palliative radiation therapy (small port)

• Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stemcell transplant (HSCT) and at least 4 weeks must have elapsed from donorlymphocyte infusion (DLI)

• Immunotherapy: At least 42 days since prior immunotherapy, including tumorvaccines and checkpoint inhibitors, and at least 21 days since receipt ofchimeric antigen receptor therapy or other modified T cell therapy

• Antileukemia Therapy***: At least 14 days, or 5 half-lives, whichever isshorter, since the completion of antileukemic therapy (for example, but notlimited to, small molecule or cytotoxic/myelosuppressive therapy), with thefollowing exceptions:

• Wah-out can be shorter for patients with rapidly progressing disease asdetermined by the treating investigator

• Hydroxyurea for cytoreduction can be initiated without restriction related totiming of study entry. Hydroxyurea can be continued concomitantly withSNDX-5613, with medical monitor approval. Patients may continue to receiveprophylactic intrathecal chemotherapy at any time at the treating physician'sdiscretion

• Hematopoietic Growth Factors: At least 7 days since the completion of therapywith short-acting hematopoietic growth factors and 14 days with long-actinggrowth factors

• Biologics (e.g., monoclonal antibody therapy): At least 90 days, or 5half-lives, whichever is shorter, since the completion of therapy with anantineoplastic biologic agent

• Steroids: At least 7 days since systemic glucocorticoid therapy, unlessreceiving physiologic dosing (equivalent to ≤10 mg prednisone daily forpatients ≥ 18 years or ≤10 mg/m^2 /day for patients

• Prior treatment with gilteritinib is allowed

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia

• Diagnosis of extra-medullary acute myeloid leukemia (AML) based on WHO 2022classification or myeloid sarcoma

• Suspected central nervous system (CNS) involvement. Patients with history ofcerebrospinal fluid (CSF) involvement must either have documented CSF clearanceprior to treatment initiation or be receiving active treatment for CNS involvement

• Participants with prior malignancy, except:

• Participants with history of adequately treated malignancy for which noanticancer systemic therapy (namely chemotherapy, radiotherapy or surgery) isongoing or required during the course of the study

• Participants who are receiving adjuvant therapy such as hormone therapy areeligible. However, participants who developed therapy related neoplasms are noteligible

• Previous known allergy/sensitivity to components of gilteritinib or SNDX-5613. Priortreatment with gilteritinib is allowed and does not exclude a patient

• Patient with known human immunodeficiency virus (HIV) or has active infection withhepatitis B virus (HBV) or hepatitis C virus (HCV). HIV-infected patients oneffective anti-retroviral therapy with undetectable viral load within 6 months areeligible for this trial. For patients with evidence of chronic HBV infection, theHBV viral load must be undetectable on suppressive therapy, if indicated.Individuals with a history of HCV infection must have been treated and cured. Forpatients with HCV infection who are currently on treatment, they are eligible ifthey have an undetectable HCV viral load

• Fridericia's corrected QT interval (QTcF) > 450 msec at time of screening

• Clinically significant ventricular arrhythmia (e.g., ventricular tachycardia,ventricular fibrillation, or Torsades de pointes)

• Uncontrolled intercurrent illness including, but not limited to, unstable anginapectoris, serious cardiac arrhythmia, myocardial infarction within 2 months prior toenrollment, New York Heart Association (NYHA) Class III or IV heart failure

• Patients with uncontrolled infection will not be enrolled until infection is treatedand under control per the principal investigator or their designee

• Any psychiatric illness that prevents patient from informed consent process

• Pregnant or breastfeeding at the time of enrollment

• Patient has a malabsorption syndrome or other condition that precludes an enteralroute of administration

• Patient has history of a cardiovascular, endocrinologic, hepatic, immunologicmetabolic, neurologic, psychiatric, pulmonary, renal disease, or any other conditionthat in the opinion of the investigator would adversely affect his/her participationin this study or interpretation of study results