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

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.

• PLX3397 (Drug), also known as Pexidartinib
• Radiation Therapy (Radiation)
• Temozolomide (Drug), also known as TMZ, Temodar

Primary outcomes

• Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group [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.]: 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.
• Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature [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.]: 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.

Secondary outcomes

• Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [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.]: 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.
• Summary of the Overall Survival in The Study Population [Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months]: 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.
• Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature [Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.]: 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
• Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.]: 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.
• Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose [Assessed from Baseline and every 8 weeks, up to 4 years 4 months]: 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.
• 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]

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group (Primary), Median, months: Combined 800 mg, 5 Days/Week 6.7 (4.5 to 11.5)
• Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature (Primary), Median, months: RP2D 7.7 (5.6 to 10.4); RP2D-0525 (Cycle 1, Day 1) 7.6 (5.5 to 10.6); RP2D-0825 7.0 (5.1 to 9.5); RP2D-0525 (Rest Period, Day 15) 6.1 (4.4 to 8.5) (p 0.456)
• Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose (Secondary), Median, months: Combined 800 mg, 5 Days/Week 6 (4.5 to 12.4) (p 0.440)
• Summary of the Overall Survival in The Study Population (Secondary), Median, months: Combined 800 mg, 5 Days/Week 13.1 (11.5 to 24.5)
• Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature (Secondary), Median, months: RP2D 18.8 (12.6 to 28.0); RP2D-0525 (Cycle 1, Day 1) 20.2 (12.9 to 31.6); RP2D-0825 17.0 (11.3 to 25.6); RP2D-0525 (Rest Period, Day 15) 16.9 (10.8 to 26.5) (p 0.389)
• Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose (Secondary), Median, months: Combined 800 mg, 5 Days/Week 14.3 (12.3 to NA) (p 0.063)
• Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose (Secondary), Count of participants, Participants: Combined 800 mg, 5 Days/Week 2 (p 0.705)
• Overview of Most Frequent System Organ Classes Reported in Phase 1b of the Modified Intent-To-Treat Population (Secondary), Count of participants, Participants: Phase 1b Dose Escalation - 600 mg/600 mg 2; Phase 1b Dose Escalation - 600 mg/800 mg 0; Phase 1b Dose Escalation - 600 mg/1000 mg 1; Phase 1b Dose Escalation - 600 mg 1; Phase 1b Dose Escalation - 800 mg/1000 mg 5; Phase 1b Dose Escalation - 800 mg 5; Phase 1b Dose Escalation - 800 mg/600 mg 1; Phase 1b Dose Escalation - 800 mg/800 mg 1; Phase 1b Dose Escation - 800 mg 3
• Overview of Most Frequent System Organ Classes Reported in Phase 2 of the Modified Intent-To-Treat Population (Secondary), Count of participants, Participants: Phase 2 - 800 mg/800 mg 24; Phase 2 - 800 mg 13; Phase 2 Total 37; Combined 800 mg, 5 Days/Week 47
• 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 (Secondary), Count of participants, Participants: Phase 1b Dose Escalation - 600 mg/600 mg 1; Phase 1b Dose Escalation - 600 mg/800 mg 1; Phase 1b Dose Escalation - 600 mg/1000 mg 0; Phase 1b Dose Escalation - 600 mg 0; Phase 1b Dose Escalation - 800 mg/1000 mg 1; Phase 1b Dose Escalation - 800 mg (5 Days) 1; Phase 1b Dose Escalation - 800 mg/600 mg 0; Phase 1b Dose Escalation - 800 mg/800 mg 1; Phase 1b Dose Escation - 800 mg (No Adjuvant Therapy) 1
• 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 (Secondary), Count of participants, Participants: Phase 2 - 800 mg/800 mg 6; Phase 2 - 800 mg 1; Phase 2 Total 7; Combined 800 mg, 5 Days/Week 9

Adverse events

Time frame: Adverse event data were collected from baseline up to 30 days after the last dose, up to 4 years 4 months.

Serious adverse events by term

Other adverse events by term

7 more terms not shown.

• Results publication: Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013 Nov 10;31(32):4085-91. doi: 10.1200/JCO.2013.49.6968. Epub 2013 Oct 7. PMID 24101040
• Results publication: Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PMID 24552317

• Study Protocol and Statistical Analysis Plan (PDF, 2017-12-14)

• Global Clinical Leader, Study director, Daiichi Sankyo