Inclusion Criteria: - Male or female patients ≥18 years old - Morphologically documented primary Acute Myeloid Leukemia (AML) or AML secondary to an antecedent hematologic disorder (e.g. MDS), as defined by World Health Organization (WHO) criteria, confirmed by pathology review at the treating institution. Bone marrow involvement is required. - In at least first relapse or refractory AML; patients ≥ 60 years old can be included if unable or unwilling to undergo induction chemotherapy for hematopoietic stem cell transplantation (HSCT) - Positive for Flt3-ITD activating mutation during Screening - ECOG performance status of 0, 1, or 2 - Adequate recovery (to at least Grade 1) from toxicity of prior therapy as follows: - ≥2 weeks for cytotoxic therapy (excluding hydroxyurea) - ≥4 half-lives for non-cytotoxic therapy - Adequate renal and hepatic function - Adequate renal function, defined as Creatinine Clearance > 60 ml/min. - Adequate hepatic function, defined as AST and ALT < 3.0X ULN and serum direct bilirubin < 1.5X ULN. Exceptions may be made for patients with elevated liver transaminases secondary to AML. - Life expectancy of at least 1 month - Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements - Women of child-bearing potential must have a negative serum pregnancy test within 7 days of initiation of dosing and must agree to use two acceptable methods of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they meet at least one of the following criteria: - Surgically sterile - Have been postmenopausal for ≥ 1 year - Have follicle stimulation hormone (FSH) levels indicative of postmenopausal state (i.e. 30-120 IU/L) Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug and for 3 months after last dose. Exclusion Criteria: - Diagnosis of acute promyelocytic leukemia - Diagnosis of chronic myelogenous leukemia in blast crisis - Receipt of HSCT within 120 days of the first dose of PLX3397, on immunosuppressive therapy post HSCT at the time of Screening, or with clinically significant graft-versus-host disease. [Use of topical steroids for ongoing skin (Graft versus Host Disease) (GVHD) is permitted) - Investigational drug use within 28 days of the first dose of PLX3397 - Relapse or refractory disease following treatment with another FLT3 tyrosine kinase inhibitor (TKI). This does NOT include patients who discontinued AC220 or other TKI due to poor tolerability or to undergo HSCT. - Disease positive for D835 mutation at Screening - A concurrent active cancer that requires non-surgical therapy (e.g. chemotherapy, radiation, adjuvant therapy). Prior history of other cancer is allowed, as long as there was no active disease within 1 year. - Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption - Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results - Women of child-bearing potential who are pregnant or breast feeding - QTcF ≥ 450 msec