Phase 1/2 Safety and Efficacy of PLX3397 in Adults With Relapsed or Refractory Acute Myeloid Leukemia (AML)

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 AML, prior-chemotherapy-related AML or AML
secondary to an antecedent hematologic disorder (e.g., Myelodysplastic Syndrome) as
defined by WHO 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 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.

- 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 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 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 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 CNS involvement of leukemia. Patients with a history of CNS involvement
may be considered after discussion with the Medical Monitor

- Patients eligible for 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 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 GVHD. 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, QTcF >450 msec for males; QTcF >470 msec for females

- Patients with a history of D835 mutations