Clinical trial NCT01790503: A Phase 1b/2 Study of PLX3397 + Radiation Therapy + Temozolomide in Patients With Newly Diagnosed Glioblastoma
Official title: An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Patients With Newly Diagnosed Glioblastoma
Keywords: glioblastoma
GBM
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Plexxikon
First posted: 2013-02-13
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Summary of the Median Progression-free Survival (mPFS) in the Combined 800 mg, 5 Days/Week Dose Group
timeFrame: 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.
measure: Summary of the Median Progression-free Survival (mPFS) in the Study Group Compared With Historical Control From Medical Literature
timeFrame: 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 outcomes:
measure: Summary of the Median Progression-free Survival (mPFS) by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
timeFrame: 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.
measure: Summary of the Overall Survival in The Study Population
timeFrame: Assessed from date of first dose administered to date of death from any cause, assessed up to 4 years 4 months
measure: Summary of the Overall Survival in the Study Group Compared With Historical Control From Medical Literature
timeFrame: Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.
measure: Summary of the Overall Survival by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
timeFrame: Assessed from date of first dose administered to the date of death from any cause, assessed up to 4 years 4 months.
measure: Summary of Best Overall Response by Subgroups in the Modified Intent-To-Treat Population on the Recommended Phase 2 Dose
timeFrame: Assessed from Baseline and every 8 weeks, up to 4 years 4 months
measure: Overview of Most Frequent System Organ Classes Reported in Phase 1b of the Modified Intent-To-Treat Population
timeFrame: Baseline up to 30 days after last dose, up to 4 years 4 months
measure: Overview of Most Frequent System Organ Classes Reported in Phase 2 of the Modified Intent-To-Treat Population
timeFrame: Baseline up to 30 days after last dose, up to 4 years 4 months
measure: 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
timeFrame: Baseline up to 30 days after last dose, up to 4 years 4 months
measure: 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
timeFrame: Baseline up to 30 days after last dose, up to 4 years 4 months
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Columbia
country: United States
facility: James Cancer Hospital/Ohio State University
state: Ohio
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.