A Phase 2 Study of PLX3397 in Patients With Recurrent Glioblastoma

• Safety-Subject incidence of adverse events [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  Subjects will take oral doses of PLX3397 twice a day. Physical examinations, vital signs, 12-lead electrocardiograms (ECG), adverse events, hematology and serum chemistry will be used to assess safety throughout the study. Adverse events will be monitored and reviewed for safety issues/abnormal changes in the above mentioned tests.
• Efficacy-6 month progression free survival rate (PFS6), median duration of response, overall survival (OS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  After discontinuation of PLX3397 for reasons other than progression of disease, patients will be followed every 3 months, or as clinically indicated, until progression of disease or death is documented.
• Efficacy-Overall response rate (ORR) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Subjects will have an MRI brain scan within 28 days of starting dosing with PLX3397 and then every 8 weeks thereafter. Response to treatment will be evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria.

The objective of this study is to evaluate the response of subjects with recurrent glioblastoma to continuous therapy of PLX3397.

• Experimental: PLX3397-Cohort 1
  10 patients with recurrent glioblastoma who require reoperation will be treated with PLX3397 for 7 days prior to surgery and their tumor tissue will be evaluated for pharmacokinetic levels and pharmacodynamic effects.
  Intervention: Drug: PLX3397
• Experimental: PLX3397-Cohort 2
  30 patients will be orally dosed with PLX3397 continuously on 28 day cycles.
  Intervention: Drug: PLX3397

Inclusion Criteria:

• Male or female patients ≥18 years old with a life expectancy of at least 8 weeks
• Radiographically proven recurrent (≥ first relapse), intracranial GBM
• For all patients, availability of at least 10 unstained slides (or archival tumor block sufficient to generate at least 10 unstained slides) from any previous GBM surgery
• Previous treatment with external beam radiation and temozolomide chemotherapy
• Before the first dose of PLX3397,adequate recovery from toxicity of prior therapy as follows:

>28 days for cytotoxic therapy >42 days for nitrosoureas >28 days for bevacizumab >7 days for non cytotoxic therapy such as interferon, tamoxifen, thalidomide, cis-retinoic acid, or erlotinib

• Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use an acceptable method 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 are either surgically sterile or have been postmenopausal for ≥1 year. Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug.
• Karnofsky performance status of ≥60
• Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.0 x 109/L, Hgb >9 g/dL, platelet count ≥50 x 109/L, AST/ALT ≤2.5x ULN, creatinine ≤1.5x ULN)
• Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements

Exclusion Criteria:

• Investigational drug use within 28 days of the first dose of PLX3397
• GBM progression within 3 months of previous radiation by RANO criteria
• History of Grade 2 (CTCAE v4) or greater acute intracranial hemorrhage
• Previous failure of bevacizumab or other VEGF therapy except in a first line setting
• History of malignant glioma with co-deletion of 1p/19q
• 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 the prior 3 years.
• 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
• QTc ≥450 msec at Screening