title: Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627).
abstract: BACKGROUND
  We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM).
  
  
  METHODS
  Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%.
  
  
  RESULTS
  A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2.
  
  
  CONCLUSIONS
  Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Pugh
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Sandrine
authors.initials: S
authors.lastname: Geinoz
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Rakesh
authors.initials: R
authors.lastname: Gaur
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Emad
authors.initials: E
authors.lastname: Youssef
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Henry
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Minhee
authors.initials: M
authors.lastname: Won
authors.affiliation: Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000069439:Dasatinib / Q000008:administration & dosage / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069439:Dasatinib
keywords: chemotherapy; dasatinib; glioblastoma; phase II; tyrosine kinase inhibitor