The purpose of this study is to evaluate the safety of study drug PLX3397 at 3 dose levels (800 mg/day, 1000 mg/day, and 1200 mg/day) and explore the efficacy in patients with relapsed or refractory acute myeloid leukemia (AML). Additional dose levels beyond 1200 mg/day may be considered based on safety and efficacy observations.

Protocol PLX108-05 is a Phase 1/2 open-label, sequential dose escalation (Part 1) followed by cohort expansion (Part 2) design at the recommended phase 2 dose established in Part 1 (i.e. 3,000 mg/day). Treatment with PLX3397 will consist of continuous oral administration in 28-day cycles until unacceptable or dose-limiting toxicity, disease progression or relapse, patient death, Investigator decision, or voluntary withdrawal.

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., Myelodysplastic Syndrome) as defined by World Health Organization criteria, confirmed by pathology review. For Cohort Expansion Phase (Part 2) only: Bone marrow involvement is required.

• Have either relapsed or refractory AML, or who have newly diagnosed Flt3-ITD positive AML but either refuse or are considered by the Investigator not to be an appropriate candidate for standard chemotherapy.

  1. Relapsed disease is defined as the reappearance of leukemia cells in the bone marrow or peripheral blood or elsewhere in the body (other tissues/organs) after the attainment of a CR.
  2. Refractory disease is defined by the failure to obtain a complete remission (CR) with a High-Dose Cytarabine (HDAC)-containing or a standard induction regimen. Patients who require two cycles of induction therapy to attain a first CR are not considered to have refractory disease.

• Positive for Flt3-ITD activating mutations during Screening. Local laboratory results must be received prior to enrollment. Patients with a history of Flt3-ITD positive disease may be considered after discussion with the Medical Monitor.

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

• Adequate recovery (to at least Grade 1) from toxicity of prior therapy as follows:

  1. ≥2 weeks for cytotoxic therapy (except hydroxyurea, which is permitted at doses of ≤5g/day during the first 2 weeks of Cycle 1) prior to C1D1.
  2. ≥4 half-lives for non-cytotoxic therapy prior to C1D1. Patients must have a wash-out period from their last chemotherapy of either ≥2 weeks OR at least 4 half-lives prior to C1D1. For patients whose most recent anti-tumor treatment regimen consisted of a multi-agent cocktail, the patient must have a wash-out period of at least 4 half-lives of the agent with the longest half-life.

• Adequate hepatic and renal function

  1. Adequate renal function, defined as Creatinine Clearance >60 mL/min or serum creatinine of ≤ 1.3 mg/dL (115 μM).
  2. Adequate hepatic function, defined as Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤3.0X Upper limit of normal (ULN) and serum direct bilirubin ≤1.5X ULN. Exceptions may be made for patients with elevated liver transaminases secondary to AML after discussion with the Medical Monitor

• 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 and for 3 months after last dose.

• Women of child-bearing potential must have a negative 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:

  1. Surgically sterile
  2. Have been postmenopausal for ≥1 year
  3. Have Follicle Stimulating Hormone (FSH) levels indicative of postmenopausal state (i.e., 30-120 IU/L) documented within 21 days of C1D1.

Sexually active men must also agree to use an acceptable method of birth control while on study drug and for at least 3 months after the last dose

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia

• Diagnosis of chronic myelogenous leukemia in blast crisis

• Presence of central nervous system (CNS) involvement of leukemia. Patients with a history of CNS involvement may be considered after discussion with the Medical Monitor

• Patients eligible for Hematopoietic Stem Cell Transplantation (HSCT) at the time of screening. However, patients who meet one or both of the following criteria may be eligible for study participation:

  1. Patients who are eligible for HSCT but with non-optimal AML disease control (i.e., blasts > 5%) may be enrolled into this study as a bridge-to-transplant.
  2. Patients with relapsed disease following a prior HSCT may be enrolled into this study as an alternative to a second HSCT or as a bridge-to-transplant regimen.

• For both Parts 1 and 2, receipt of HSCT within 60 days of the first dose of PLX3397 is an exclusion criterion. Patients on immunosuppressive therapy post HSCT, or with clinically significant graft-versus-host disease are excluded from Part 1. (Use of topical steroids for ongoing skin Graft vs. host disease [GVHD] is permitted). Patients for Part 1 must have a wash-out period of ≥2 weeks or at least 4 half-lives from their last systemic immunosuppressive treatment for Graft vs. host disease. Patients for Part 2 may be receiving systemic immunosuppressive treatment for management of GVHD at the time of screening and enrollment

• Investigational drug use within 28 days of the first dose of PLX3397

• For Cohort Expansion Phase (Part 2) only: Patients who are positive for the D835 mutation at Screening are excluded.

• 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 is no active disease within 1 year of the first dose of PLX3397.

• Refractory nausea and vomiting, malabsorption, biliary shunt significant bowel resection, GVHD affecting the gut, or any other condition 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

• At Screening, QT interval, Frederica's formula (QTcF) >450 msec for males; QTcF >470 msec for females

• Patients with a history of D835 mutations

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.