Inclusion Criteria:

- Male or female patients ≥18 years old

- Morphologically documented primary Acute Myeloid Leukemia (AML), prior
chemotherapy-related 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 for
Cohort Expansion Phase (Part 2)only.

- 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 prior to C1D1 for cytotoxic therapy (excluding hydroxyurea, which is
permitted at doses less than or equal to 5 g/day during first 2 weeks of cycle
1)

- ≥4 half-lives for non-cytotoxic therapy prior to C1D1; washout period from last
chemotherapy of at least 2 weeks OR at least 4 half-lives prior to C1D1.

- 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) Sexually active men 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

- Presence of CNS involvement of leukemia [discuss with Medical Monitor]

- Eligible for hematopoietic stell cell transplant (HSCT) at time of screening.
However, patients who meet both of the following criteria may be eligible for study
participation:

1. eligible for HSCT but with non-optimal AML disease control (i.e., blasts greater
than 5 percent) may be enrolled as bridge-to-transplant.

2. relapsed disease following prior HSCT may be enrolled as alternative to second
HSCT or as bridge-to-transplant regimen.

- Receipt of HSCT within 60 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

- For Cohort Expansion Phase (Part 2) only: 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