A Phase 1b/2 Study of PLX3397 + Radiation Therapy + Temozolomide in Patients With Newly Diagnosed Glioblastoma

Study Overview
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Brief Summary
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The study objectives are to assess the potential for PLX3397 to improve the efficacy of standard of care radiation therapy (RT) + temozolomide in patients with newly diagnosed glioblastoma (GBM).

Detailed Description
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Study drug will be administered twice daily for 7 days prior to the initiation of RT (radiation therapy)and will continue twice daily during the course of RT. The RT schedule will be once daily for 5 days per week for 6 weeks (total radiation dose of 60 Gy. Oral temozolomide will be administered once daily (7 days per week) for the duration of RT. Four weeks after the completion of the course of RT, patients will be started on once-daily adjuvant temozolomide (Day 1-5 of a 28 day cycle) and PLX3397 twice daily (28 days of a 28 day cycle) for up to 12 cycles in the absence of progressive disease or unacceptable toxicities. After discontinuation of study drug, patients will continue to be followed for OS every 6 months. For patients participating in the run-in Phase 1b of the study, intra patient dose escalation will be permitted after a RP2D has been established. The Phase 2 portion of the study will enroll patients to be treated with PLX3397 at RP2D. For the Phase 1b portion of the study, 2 cohorts (800 mg/day and 1000 mg/day) are planned to be enrolled at approximately 7-10 sites. Each cohort will consist of approximately 7 patients. Therefore, a minimum of 14 patients are planned to be enrolled in Phase 1b. Additional patients may be required for replacement patients, or if lower dose cohorts (600 mg or 400 mg) are required. For the Phase 2 portion of the study, enrollment is planned to include approximately 44 patients.

Official Title
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An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma

Conditions
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Patients With Newly Diagnosed Glioblastoma

Intervention / Treatment
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* Drug: PLX3397
* Radiation: Radiation Therapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥18 years old. Histologically confirmed definitive GBM or gliosarcoma by partial or complete surgical resection (i.e. not by biopsy only) within 5 weeks prior to PLX3397 administration (C1D1). Tumor must have a supratentorial component. For all patients, availability of a surgical paraffin tumor block sufficient to generate at least 20 unstained slides; or, if a paraffin tumor block is unavailable, at least 20 unstained slides. The patient must have recovered from the effects of surgery, post-operative infection, and other complications before study registration. A diagnostic contrast-enhanced MRI or CT scan of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy, within 28 days (preferably 14 days) prior to C1D1. Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality. Patients must receive RT at the participating institution. Women of child-bearing potential must have a negative pregnancy test within 14 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, and for 3 months after the last dose. Karnofsky performance status of ≥70. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.5x 109/L, Hgb >10 g/dL, platelet count ≥100 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: Evidence of recurrent GBM or metastases detected outside of the cranial vault. Investigational drug use within 28 days of the first dose of PLX3397 or concurrently. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment. Prior radiation or chemotherapy for glioblastoma or glioma. Prior chemotherapy or radiosensitizers for cancer of the head and neck (except for T1 glottic cancer) that would result in an overlap of radiation fields. Prior allergic reaction to temozolomide. History of Grade 2 (CTCAE v4) or greater acute intracranial hemorrhage. Active cancer (either concurrent or within the last 3 years) that requires non-surgical therapy (e.g. chemotherapy or radiation therapy), with the exception of surgically treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix. Chronic active hepatitis B or C. Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption of study drug. 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 and ≥470 msec for females.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b dose escalation - 600mg/day PLX3397 cohort<br>600mg/day PLX3397, Radiation Therapy, and Temozolomide | Drug: PLX3397<br> <br> * Other names: Pexidartinib;Radiation: Radiation Therapy<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar;|
| Experimental: Phase 1b dose escalation - 800mg/day PLX3397<br>800mg/day PLX3397, Radiation Therapy, and Temozolomide | Drug: PLX3397<br> <br> * Other names: Pexidartinib;Radiation: Radiation Therapy<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar;|
| Experimental: Phase 1b dose escalation - 1000 mg/day PLX3397 cohort<br>1000 mg/day PLX3397, Radiation Therapy, and Temozolomide | Drug: PLX3397<br> <br> * Other names: Pexidartinib;Radiation: Radiation Therapy<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar;|
| Experimental: Phase 2 - Recommended phase 2 dose of PLX3397<br>Recommended phase 2 dose of PLX3397 (800mg/day), Radiation therapy, and Temozolomide | Drug: PLX3397<br> <br> * Other names: Pexidartinib;Radiation: Radiation Therapy<br> <br> Drug: Temozolomide<br> <br> * Other names: Temodar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group | Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method. | Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months. | 
| Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature | mPFS was based on model parameters estimated by maximum likelihood with a Newton-Raphson algorithm. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure. | Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose | Progression was determined by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS) was analyzed based on the non-parametric Kaplan-Meier method. mPFS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome. | Assessed from date of first dose administered to date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years 4 months. | 
| Summary of the Overall Survival in The Study Population | Overall Survival (OS) was defined as the number of days from the first day of treatment (C1D1) to the date of death and analyzed using a non-parametric Kaplan Meier method. | Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months | 
| Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature | Overall Survival was calculated using a parametric model. The Radiation Therapy Oncology Group (RTOG) 0525 study was the main historical control used for statistical analysis. Additionally, RTOG-0825 was also used to support this outcome measure | Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months. | 
| Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose | Overall Survival was calculated using a non-parametric Kaplan-Meier analysis method. Median OS was analyzed by age group, extent of surgery, baseline Karnofsky Performance Status (KPS), and O6-methylguanine-DNA methyltransferase status (MGMT). The scale range for the baseline Karnofsky Performance Status is from 0-100, with 0 indicating that the participant is dead and 100 indicating that the participant is Normal no complaints, no evidence of disease. The higher the number, the better the outcome. | Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months. | 
| Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose | Best Overall Response (based on the RANO response) was defined as the highest overall response recorded from the start of study treatment until the end of treatment. Per the Response Assessment in Neuro-Oncology (RANO) criteria for measurable lesions and assessed by Cranial MRI scan, summarized as: Complete Response (CR), Disappearance of all enhancing disease (measurable and non-measurable); Partial Response (PR), >=50% decrease of all measurable enhancing lesions; Stable disease, does not qualify for complete response, partial response, or progression, and progression, >25% increase in enhancing lesions despite stable or increasing steroid use or any new lesions. | Assessed from Baseline and every 8 weeks, up to 4 years 4 months | 
| Overview of Most Frequent System Organ Classes Reported in Phase 1b of the Modified Intent-To-Treat Population |  | Baseline up to 30 days after last dose, up to 4 years 4 months | 
| Overview of Most Frequent System Organ Classes Reported in Phase 2 of the Modified Intent-To-Treat Population |  | Baseline up to 30 days after last dose, up to 4 years 4 months | 
| Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 1b of the Modified Intent-To-Treat Population |  | Baseline up to 30 days after last dose, up to 4 years 4 months | 
| Number of Patients With Clinically Significant Abnormal Chemistry and Hematology Values Reported as Adverse Events by Preferred Term in Phase 2, the Combined RP2D Groups in Phase 1b, and in the Study Overall Modified Intent-To-Treat Population |  | Baseline up to 30 days after last dose, up to 4 years 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glioblastoma, GBM