title: Phase I/II study of atrasentan, an endothelin A receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Endothelins and their cell membrane receptors (ET(A)R and ET(B)R) are implicated in neoplastic pathogenesis. atrasentan, a potent, selective ET(A)R antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis. This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin.
  
  
  METHODS
  Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non-small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute Common Toxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m(2)) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. A fixed 10 mg daily oral dose ofAtrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre- and post-atrasentan) in the first 10 patients.
  
  
  RESULTS
  All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean +/- SD, 21.2 +/- 4.5 L/h versus 21.3 +/- 4.9 L/h) for pre- and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities > or = 10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%.
  
  
  CONCLUSIONS
  Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non-small cell lung cancer were comparable with studies of chemotherapy alone.
authors.affiliation: Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. Alberto.Chiappori@moffitt.org
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Chiappori
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Rodriguez
authors.forename: David
authors.initials: D
authors.lastname: Boulware
authors.forename: Rachna
authors.initials: R
authors.lastname: Kapoor
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Neuger
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Barbara
authors.initials: B
authors.lastname: Padilla
authors.forename: Michelle
authors.initials: M
authors.lastname: Burton
authors.forename: Charles
authors.initials: C
authors.lastname: Williams
authors.forename: George
authors.initials: G
authors.lastname: Simon
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077868:Atrasentan; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000556:secondary; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011759:Pyrrolidines / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D016190:Carboplatin; D017239:Paclitaxel; D000077868:Atrasentan