Regorafenib in Combination With Venetoclax and Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia

Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative * Age: ≥ 18 years * Eastern Cooperative Oncology Group (ECOG) ≤ 2 * Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease who are ineligible for therapies known to be effective for treatment of their AML * Patients with extramedullary disease may be included if they also have marrow involvement * Patients with acute promyelocytic leukemia (APL) will not be eligible * Patients with R/R myelodysplastic syndrome (MDS)/AML, as defined by the presence of 10 - 19% blasts, are also eligible at the discretion of the principal investigator (PI) * Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy * Ability to swallow pills * White blood cells (WBC) ≤ 25 x 10\^9/L prior to initiation of study therapy. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required (To be performed within 14 days prior to day 1 of protocol therapy) * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (To be performed within 14 days prior to day 1 of protocol therapy) * Aspartate aminotransferase (AST) ≤ 3.0 x ULN (To be performed within 14 days prior to day 1 of protocol therapy) * Alanine aminotransferase (ALT) ≤ 3.0 x ULN (To be performed within 14 days prior to day 1 of protocol therapy) * Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula (To be performed within 14 days prior to day 1 of protocol therapy) * International normalized ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN (To be performed within 14 days prior to day 1 of protocol therapy) * Activated partial thromboplastin Time (aPTT) ≤ 1.5 x ULN (To be performed within 14 days prior to day 1 of protocol therapy) * Corrected QT interval by Fredericia (QTcF) ≤ 480 ms based on Fridericia's formula. (To be performed within 14 days prior to day 1 of protocol therapy) Note: To be performed within 28 days prior to day 1 of protocol therapy * Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. (To be performed within 14 days prior to day 1 of protocol therapy) * Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 4 months (males) and 7 months (females) after the last dose of protocol therapy * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only) Exclusion Criteria: * Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol therapy * Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter) prior to day 1 of protocol therapy with the following exceptions: * Subjects will be allowed to have been on venetoclax and/or azacitidine at screening and remain on it through treatment start * Hydroxyurea is allowed prior to treatment and through cycle 1 for control of rapidly progressing leukemia * Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior to day 1 of protocol therapy * Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 3 days prior to initiation of and during study treatment * Systemic steroid therapy \> 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 14 days. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted. Steroids given for infusion prophylaxis or infusion reactions should not count towards this maximum * Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment * Evidence or history of bleeding diathesis or coagulopathy * Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment within 6 months of informed consent * Presence of a non-healing wound, non-healing ulcer, or bone fracture * Major surgical procedure or significant traumatic injury within 28 days before start of study medication * Pleural effusion or ascites that causes respiratory compromise ( ≥ National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] version 5.0 grade 2 dyspnea) * Patients with blast phase chronic myeloid leukemia (CML) * Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML) * Active central nervous system (CNS) disease * Active graft versus host disease (GVHD) * Unstable cardiac disease as defined by one of the following: * Cardiac events such as myocardial infarction (MI) within the past 6 months * Uncontrolled atrial fibrillation or hypertension * No measurable disease in the bone marrow * Active diarrhea * Gastrointestinal disorder that interferes with oral drug absorption such as malabsorption syndrome * History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent * Uncontrolled active infection * Clinically significant uncontrolled illness * Diagnosis of Gilbert's disease * Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Females only: Pregnant or breastfeeding * Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)