University of California, San Francisco, San Francisco, CA
Nicholas A. Butowski , Howard Colman , John Frederick De Groot , Antonio Marcilio Padula Omuro , Lakshmi Nayak , Timothy F. Cloughesy , Adhirai Marimuthu , Arie Perry , Joanna J Phillips , Brian West , Michael Prados , Keith B. Nolop , Henry H Hsu , Keith L. Ligon
Background: PLX3397 is an oral, small molecule that potently and selectively inhibits CSF1R, Kit, and Flt3-ITD kinases. CSF1R is expressed on microglia/macrophages and tumor cells within glioblastoma (GB). Many glioma cell lines express the CSF1R ligands, CSF-1 and IL-34 and the KIT ligand, SCF, and depletion of microglia in preclinical GB models reduces tumor burden and spread. Methods: This study of recurrent GB measured the 6-month PFS rate (PFS6), median duration of response, overall response rate (ORR), overall survival (OS), safety, and plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD) during PLX3397 treatment. Results: 38 recurrent GB patients were treated with PLX3397 at 1000 mg daily, with Cohort 1 (14 patients) treated 7 days in advance of recurrent surgery and Cohort 2 (24 patients) without surgery. PLX3397 was well tolerated; common (>10%) treatment-related adverse events included fatigue, constipation, nausea, hair color change, elevation in AST/ALT, anorexia, and headache. The primary endpoint of PFS6 was 11.4% with no complete or partial responses. 7/38 (18%) of patients experienced stable disease.Plasma PK Cmax was median 8090 ng/mL (range 3100-13400) with Tmax of 2 hr. Cohort 1 tumor tissue PK was median 5500 ng/g (range 1320-69400). PD effects observed in blood in both Cohorts included elevated plasma CSF-1 and reduced CD14dim/CD16+ monocytes. In pre-surgical patients (Cohort 1), tissue PD effects observed included possible changes in tumor macrophage/microglia morphology, IBA1 IHC, FACS, and pERK IHC compared to control patient tissues. PDGFRA amplification was seen in 13/36 archival samples. Conclusions: PLX3397 is a potent inhibitor of tumor-associated macrophages and microglia, readily entered GB tissue, and demonstrated expected PD effects. As a single agent, PLX3397 showed no significant improvement in PFS, although further research toward identifying a responsive subset of GB patients is ongoing. PLX3397 is well-tolerated and its safety profile is conducive to testing its combination with other treatments; A Phase 2 trial combining PLX3397 with RT and Temodar in newly diagnosed GB has been initiated. Clinical trial information: NCT01349036.
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