PLX3397, Radiation Therapy, and Antihormone Therapy in Treating Patients With Intermediate- or High-Risk Prostate Cancer

PRIMARY OBJECTIVES:

I. To conduct a phase I, dose escalation trial with a primary objective of establishing the
maximum tolerated dose (MTD) and the dose limiting toxicity (DLT).

SECONDARY OBJECTIVES:

I. To assess the effects of radiation therapy (RT), androgen deprivation therapy (ADT), and
PLX3397 (at its MTD) on tumor-associated macrophages (TAMs) in the prostate biopsy after
treatment.

OUTLINE: This is a dose-escalation study of multitargeted tyrosine kinase inhibitor PLX3397.

Patients receive multitargeted tyrosine kinase inhibitor PLX3397 orally (PO) twice daily
(BID) for 6 months, undergo radiation therapy for 2 months daily (Monday-Friday) beginning at
month 3, and undergo ADT with leuprolide acetate, goserelin acetate, or degarelix injections
in any month.

After completion of study treatment, patients are followed up at 20-30 days and then every 12
weeks thereafter.

Inclusion Criteria:

- Pathologically confirmed diagnosis of prostate adenocarcinoma

- Must have archival prostate biopsy tissue available

- Intermediate risk or high risk prostate cancer patients who are candidates for
radiation therapy:

- Gleason 7-10 or

- Clinical or pathological > T2b disease or

- Prostate-specific antigen (PSA) >= 10 ng/mL

- No evidence of metastatic disease by clinical and radiological staging

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1

- No standard contraindications to radiation therapy including prior significant
radiation therapy, inflammatory bowel disease, irritable bowel syndrome or collagen
vascular disease

- Prior history of up to 8 weeks of androgen deprivation therapy defined as
luteinizing-hormone releasing hormone (LHRH) or other medical castration therapy prior
to registration is acceptable; this will be in addition to the 6 months of ADT on
study

- Life expectancy of at least 3 months

- Absolute neutrophil count >= 1,500 cells/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 9.0 g/dL

- Serum creatinine =< 1.5 x upper limit of normal (ULN); Note: If serum creatinine is >
1.5 x ULN, subject is eligible if the calculated creatinine clearance is >= 50 mL/min

- Must have ability to take oral medication

- No distant metastases as evaluated by a bone scan and computed tomography (CT) of the
pelvis (within 90 days of enrollment)

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy, radiation
therapy, antibody based therapy, etc.) are excluded

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures

- Ability to understand and willingness to sign a written informed consent document

- Willingness to be treated with radiation therapy and androgen deprivation therapy

Exclusion Criteria:

- Investigational drug use within 28 days of the first dose of PLX3397 or concurrently

- At screening QT interval corrected by Fridericia's formula (QTcF) >= 450 msec

- 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

- Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel
resection that would preclude adequate absorption of study drug

- History of chronic active hepatitis B or C

- Active cancer (either concurrent or within the last 3 years) that requires nonsurgical
therapy (e.g. chemotherapy or radiation therapy), with the exception of surgically
treated basal or squamous cell carcinoma of the skin, or melanoma in situ

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 X ULN or > 5 X
ULN in the presence of liver metastases

- Total bilirubin > 2 mg/dL (in the absence of Gilbert's disease)

- Current treatment with anti-androgen is allowed for a maximum of one month to prevent
flare response with ADT