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

Inclusion Criteria: * Pathologically confirmed diagnosis of prostate adenocarcinoma * Must have confirmed viable archival prostate biopsy tissue available as per Section 8.1 (this will be collected for patients going on study after the MTD has been reached * Intermediate or high risk prostate cancer patients who are candidates for radiation therapy: * Gleason \>7 or * Clinical or pathological \> T2b disease or * 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 lutenizing-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 * Adequate hematologic, hepatic, and renal function as defined by: * Absolute neutrophil count ≥ 1.5 × 109/L * Hemoglobin \> 10 g/dL * Platelet count ≥ 100 × 109/L * AST and ALT ≤ upper limit of normal (ULN) * TBil and DBil ≤ ULN with an exception of patients with confirmed Gilbert's syndrome. For patients with confirmed Gilbert's syndrome, the TBil should be ≤ 1.5 × ULN * Serum creatinine ≤ 1.5 × ULN * Must have ability to take oral medication * 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 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 * Known active or chronic human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection, or positive hepatitis B (Hep B) surface antigen. Prior hepatitis infection that has been treated with highly effective therapy with no evidence of residual infection and with normal liver function (ALT, AST, total and direct bilirubin ≤ ULN) is allowed. * Hepatobiliary diseases including biliary tract diseases, autoimmune hepatitis, inflammation, fibrosis, cirrhosis of liver caused by viral, alcohol, or genetic reasons. Gilbert's disease is allowed if TBil is ≤ 1.5 × ULN. * 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 insitu. * AST/ALT \> 2.5X ULN or \>5X ULN in the presence of liver metastases. * Current treatment with anti-androgen is allowed for a maximum of one month to prevent flare response with ADT * Concomitant use of acid reducing agents (e.g., proton pump inhibitors, H2 receptor antagonists, antacids) * Concomitant use of strong and moderate CYP3A4 inhibitors and inducers * Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of the study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)