• 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 Health Organization (WHO) classification:

‣ Relapsed or Refractory Acute Myeloid Leukemia with the following:

∙ Refractory disease classified as having received 2 cycles of intensive induction or 2 cycles of hypomethylating agent (HMA) + Venetoclax with persistent disease of ≥ 5% blasts in the bone marrow and/or reappearance of peripheral blasts

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

⁃ NPM1 mutation, MLL gene rearrangement and any other mutation that has proven HOXA-MEIS1 overexpression (NUP98, UBTF-TD, MLL-PTD and any others that have supporting literature)

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

• Not suitable for immediate myeloablative/intensive chemotherapy based on investigator assessment of age, comorbidities, local guidelines, institutional practice (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 × upper limit 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 on Modification of Diet in Renal Disease (MDRD) formula, by local laboratory)

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

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

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

• Participants capable of impregnating others who are having intercourse with people of childbearing potential must agree to abstain from intercourse or have their partner use 2 forms of contraception from the screening visit until 90 days after the last dose of study treatment. They must also refrain from sperm donation from the 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 discontinued therapy 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 14 days from local palliative radiation therapy (small port)

⁃ Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant (HSCT) and at least 4 weeks must have elapsed from donor lymphocyte infusion (DLI)

⁃ Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy

⁃ Antileukemia Therapy\*\*\*: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy (for example, but not limited to, small molecule or cytotoxic/myelosuppressive therapy), with the following exceptions:

⁃ Wah-out can be shorter for patients with rapidly progressing disease as determined by the treating investigator

⁃ Hydroxyurea for cytoreduction can be initiated without restriction related to timing of study entry. Hydroxyurea can be continued concomitantly with SNDX-5613, with medical monitor approval. Patients may continue to receive prophylactic intrathecal chemotherapy at any time at the treating physician's discretion

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

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

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

∙ Prior treatment with gilteritinib is allowed