title: Multicenter phase 2 study of patupilone for recurrent or progressive brain metastases from non-small cell lung cancer.
abstract: BACKGROUND
  Treatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.
  
  
  METHODS
  Adult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.
  
  
  RESULTS
  Fifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.
  
  
  CONCLUSIONS
  This is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.
authors: Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Lakshmi
authors: L
authors: Nayak
authors: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Lisa M
authors: LM
authors: DeAngelis
authors: Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.
authors: H Ian
authors: HI
authors: Robins
authors: Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors: Ramaswamy
authors: R
authors: Govindan
authors: Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.
authors: Shirish
authors: S
authors: Gadgeel
authors: Division of Hematology and Oncology, Davis Comprehensive Cancer Center, University of California, Sacramento, California.
authors: Karen
authors: K
authors: Kelly
authors: Norris Cotton Cancer Center/Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors: James R
authors: JR
authors: Rigas
authors: Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors: David M
authors: DM
authors: Peereboom
authors: Department of Neurology, Columbia University Medical Center/New York Presbyterian, New York, New York.
authors: Steven S
authors: SS
authors: Rosenfeld
authors: Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.
authors: Alona
authors: A
authors: Muzikansky
authors: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors: Ming
authors: M
authors: Zheng
authors: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors: Patrick
authors: P
authors: Urban
authors: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Lauren E
authors: LE
authors: Abrey
authors: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors: Antonio
authors: A
authors: Omuro
authors: Center For Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Patrick Y
authors: PY
authors: Wen
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D004334:Drug Administration Schedule; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C093788:epothilone B
keywords: brain metastases; chemotherapy; non-small cell lung cancer; patupilone; recurrent metastases