Actr-20. Initial Results of Plx108-08: an Open Label Phase 1b/2 Study of Orally Administered Pexidartinib (plx3397) in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
Year: 2016
Type: conference-abstract
Abstract: Pexidartinib (PEX) is a small molecule inhibitor of KIT and the CSF1 receptor expressed on microglia, blood vessels, and glioblastoma (GBM) tumor cells. A prior recurrent GBM study showed that PEX readily crossed the blood-brain barrier. Preclinical studies indicate that PEX effects on tumor and microenvironment may sensitize newly diagnosed GBM to standard therapy. Phase Ib dose escalation determined the recommended Phase II dose (RP2D) with XRT and TMZ. Phase II primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS) and safety. Patient inclusion/exclusion were designed to replicate the RTOG 0525 control arm, which was used as historical control. PEX 400mg BID daily 5 days/week during and 7 days/week after XRT was identified as the RP2D. In Phase II, 42 of 44 patients were evaluable. Prognostic factors showed good concordance between PEX population and the RTOG 0525 control arm. 28 of 42 patients experienced a PFS event. Median PFS from registration is 9.7 months in PEX patients (95% CI 7.3, 13.2) vs. 7.5 months in historical controls (p= 0.035)(HR 0.71, (95% CI 0.49, 1.03)). Initial OS analyses show 8 of 42 PEX patients with events at 9-months vs. 13.1 expected deaths in controls (p=0.046) and 12-month OS events of 9 (PEX) vs. 16.8 (expected control) (p=0.029). Estimated mOS for PEX is 25.1 months (95% CI 15.7, 41.0) vs. 18.9 months controls (p=0.108)(HR 0.72, 95% CI 0.43, 1.21), and updated data will be presented as additional events occur. PEX was well tolerated, with most common drug-related toxicities including neutropenia and increased ALT/AST. PEX 400mg BID can be safely combined with XRT/TMZ in newly diagnosed GBM. Initial Phase II results suggest promising effects of PEX in improving PFS and OS compared to robust, well-matched historical controls. Further investigation of PEX in randomized trials is warranted.
Source: Neuro-Oncology
Institutions: University of Utah, Northwestern University, Henry Ford Health, Massachusetts General Hospital, Seattle Cancer Care Alliance, University of Washington, Fred Hutch Cancer Center, Beth Israel Deaconess Medical Center, The Ohio State University Wexner Medical Center, Harvard University, Dana-Farber Cancer Institute, Columbia University Irving Medical Center, Huntsman Cancer Institute, Clinipace (United States), Plexxikon (United States)
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2558068193