title: Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study.
abstract: BACKGROUND
  The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development.
  
  
  METHODS
  We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.
  
  
  RESULTS
  A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values.
  
  
  CONCLUSIONS
  PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: John F
authors.initials: JF
authors.lastname: De Groot
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Omuro
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Nayak
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Sam
authors.initials: S
authors.lastname: Haidar
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Jason
authors.initials: J
authors.lastname: Huse
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Joanna
authors.initials: J
authors.lastname: Phillips
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Keith B
authors.initials: KB
authors.lastname: Nolop
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Henry H
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Annette M
authors.initials: AM
authors.lastname: Molinaro
authors.affiliation: University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D047368:Tumor Burden
chemical_list: D000631:Aminopyridines; D014408:Biomarkers, Tumor; D011758:Pyrroles; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C000600259:pexidartinib
keywords: CSF1R; PLX3397; glioblastoma; glioma; microglia