A Phase 2 Study of PLX3397 in Patients With Recurrent Glioblastoma

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

Official Title
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A Phase 2 Study of Orally Administered PLX3397 in Patients With Recurrent Glioblastoma

Conditions
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Recurrent Glioblastoma

Intervention / Treatment
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* Drug: PLX3397


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥18 years old with a life expectancy of at least 8 weeks Radiographically proven recurrent (≥ first relapse), intracranial Glioblastoma (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, Aspartate aminotransferase/Alanine aminotransferase (AST/ALT) ≤2.5x Upper Limit of Normal (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 Response Assessment in Neuro-Oncology (RANO) criteria History of Grade 2 Common Toxicity Criteria for Adverse Events (CTCAE v4) or greater acute intracranial hemorrhage Previous failure of bevacizumab or other vascular endothelial growth factor (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 corrected QT interval (QTc) ≥450 msec at Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLX3397-Cohort 1<br>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. | Drug: PLX3397<br>* Capsules administered once or twice daily, continuous dosing<br>* Other names: Pexidartinib;|
| Experimental: PLX3397-Cohort 2<br>30 patients will be orally dosed with PLX3397 continuously on 28 day cycles. | Drug: PLX3397<br>* Capsules administered once or twice daily, continuous dosing<br>* Other names: Pexidartinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Response Rates in Participants on Treatment With PLX3397 | Response to treatment was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria. All participants were evaluated for progression free survival (PFS), and overall survival (OS). The six-month PFS rate was defined as the number of subjects with PFS of at least 6-month duration, with PFS measured from the first day of treatment (Cycle 1, Day 1) to the date of the first documented disease progression or date of death, whichever occurs first, over a 6-month period and evaluated using the Kaplan Meier method. The rate of OS was defined as the number of subjects that survived until study exit. | 6 months post dose | 
| Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters, include time to maximum concentration (Tmax) and will be calculated from the Cycle 1, Day 15 values. | Pre-dose and up to 6 post dose during cycle 1, Day 15 | 
| Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include maximum concentration (Cmax) and will be calculated from the Cycle 1, Day 15 values. | Pre-dose and up to 6 post dose during cycle 1, Day 15 | 
| Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-4 hours (AUC0-4), and will be calculated from the Cycle 1, Day 15 values. | Pre-dose and up to 6 post dose during cycle 1, Day 15 | 
| Mean Plasma Pharmacokinetic Parameters of PLX3397 After Oral Administration of 1000 mg/Day - Cycle 1 Day 15 | A noncompartmental method of analysis was used to analyze the plasma concentrations of PLX3397. Mean plasma pharmacokinetic parameters include an assessment of area under the curve over 0-6 hours (AUC0-6), and will be calculated from the Cycle 1, Day 15 values. | Pre-dose and up to 6 post dose during cycle 1, Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence (Number and Percentage of Participants) With Treatment-Emergent Adverse Events Related to Study Drug Occurring in ≥10% Participants During Treatment With PLX3397 (Safety Population) |  | Up to 1 year post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, brain cancer