PMID- 26449250
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20220409
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 18
IP  - 4
DP  - 2016 Apr
TI  - Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in 
      recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium 
      phase II study.
PG  - 557-64
LID - 10.1093/neuonc/nov245 [doi]
AB  - 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. CONCLUSION: 
      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.
CI  - (c) The Author(s) 2015. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Butowski, Nicholas
AU  - Butowski N
AD  - 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.).
FAU - Colman, Howard
AU  - Colman H
AD  - 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.).
FAU - De Groot, John F
AU  - De Groot JF
AD  - 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.).
FAU - Omuro, Antonio M
AU  - Omuro AM
AD  - 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.).
FAU - Nayak, Lakshmi
AU  - Nayak L
AD  - 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.).
FAU - Wen, Patrick Y
AU  - Wen PY
AD  - 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.).
FAU - Cloughesy, Timothy F
AU  - Cloughesy TF
AD  - 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.).
FAU - Marimuthu, Adhirai
AU  - Marimuthu A
AD  - 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.).
FAU - Haidar, Sam
AU  - Haidar S
AD  - 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.).
FAU - Perry, Arie
AU  - Perry A
AD  - 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.).
FAU - Huse, Jason
AU  - Huse J
AD  - 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.).
FAU - Phillips, Joanna
AU  - Phillips J
AD  - 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.).
FAU - West, Brian L
AU  - West BL
AD  - 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.).
FAU - Nolop, Keith B
AU  - Nolop KB
AD  - 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.).
FAU - Hsu, Henry H
AU  - Hsu HH
AD  - 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.).
FAU - Ligon, Keith L
AU  - Ligon KL
AD  - 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.).
FAU - Molinaro, Annette M
AU  - Molinaro AM
AD  - 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.).
FAU - Prados, Michael
AU  - Prados M
AD  - 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.).
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P50 CA097257/CA/NCI NIH HHS/United States
GR  - R01 NS081117/NS/NINDS NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20151008
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Aminopyridines)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Pyrroles)
RN  - 0 (Receptors, Granulocyte-Macrophage Colony-Stimulating Factor)
RN  - 6783M2LV5X (pexidartinib)
SB  - IM
MH  - Administration, Oral
MH  - Aminopyridines/pharmacokinetics/*therapeutic use
MH  - Biomarkers, Tumor/metabolism
MH  - Blood-Brain Barrier/drug effects
MH  - Brain Neoplasms/*drug therapy/metabolism/pathology
MH  - Cohort Studies
MH  - Female
MH  - Follow-Up Studies
MH  - Glioblastoma/*drug therapy/metabolism/pathology
MH  - Humans
MH  - Immunoenzyme Techniques
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy/metabolism/pathology
MH  - Neoplasm Staging
MH  - Prognosis
MH  - Pyrroles/pharmacokinetics/*therapeutic use
MH  - Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/*antagonists & 
      inhibitors
MH  - Tissue Distribution
MH  - Tumor Burden
PMC - PMC4799682
OTO - NOTNLM
OT  - CSF1R
OT  - PLX3397
OT  - glioblastoma
OT  - glioma
OT  - microglia
EDAT- 2015/10/10 06:00
MHDA- 2016/12/15 06:00
PMCR- 2017/04/01
CRDT- 2015/10/10 06:00
PHST- 2015/05/14 00:00 [received]
PHST- 2015/09/03 00:00 [accepted]
PHST- 2015/10/10 06:00 [entrez]
PHST- 2015/10/10 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - nov245 [pii]
AID - 10.1093/neuonc/nov245 [doi]
PST - ppublish
SO  - Neuro Oncol. 2016 Apr;18(4):557-64. doi: 10.1093/neuonc/nov245. Epub 2015 Oct 8.