title: A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer.
abstract: BACKGROUND
  There are few effective treatment options for leptomeningeal metastasis (LM) in non-small-cell lung cancer (NSCLC). This study assessed the feasibility of high-dose gefitinib in patients with LM from NSCLC harboring EGFR mutations or prior systemic response to EGFR-TKI.
  
  
  METHODS
  This phase I open-label trial of a novel gefitinib dosing schedule employed a 3+3 design. Eligible NSCLC patients with LM had known EGFR mutations and/or prior response to EGFR-TKI. Patients alternated 2 weeks of high-dose daily gefitinib (dose levels: 750 mg, 1000 mg, 1250 mg) with 2 weeks of maintenance therapy (500 mg daily). Primary endpoints were safety and toxicity. Secondary endpoints included overall survival (OS), neurological progression-free survival, radiological response, and cytological response in cerebrospinal fluid (CSF).
  
  
  RESULTS
  Seven patients were treated: 3 at 750 mg dose level, 4 at 1000 mg dose level. There were no DLTs at the 750 mg dose level, and one DLT (toxic epidermal necrolysis) at the 1000 mg dose level. The study was closed due to slow accrual. Median neurological PFS was 2.3 months (range 1.6-4.0 months); median OS was 3.5 months (range 1.6-5.1 months). Though there were no radiologically documented remissions of LM disease, four patients had improvement in neurological symptoms. One patient cleared their CSF of NSCLC cells, while 2 others had decrease in malignant cells in CSF.
  
  
  CONCLUSIONS
  Although the MTD was not defined due to slow accrual, this study provides important information about the tolerability and CSF penetration of high-dose gefitinib as a therapeutic option for modest palliation for NSCLC patients with LM and a known EGFR mutation.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Jackman
authors.affiliation: Georgetown University School of Medicine, Washington, DC USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Cioffredi
authors.affiliation: Eurofins Medinet B.V., Breda, The Netherlands.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Farhana
authors.initials: F
authors.lastname: Sharmeen
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Morse
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Lucca
authors.affiliation: Harvard Medical School, Boston, MA.|Stephen E. & Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Marcoux
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rabin
authors.affiliation: Smilow Cancer Hospital at Yale-New Haven, Yale Cancer Center, New Haven, CT, USA.|Yale University, New Haven, CT, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.affiliation: Department of Neurosciences, Translational Neuro-Oncology Laboratories, Moores UCSD Cancer Center, University of California, San Diego, La Jolla CA, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib