title: A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  The primary aim of this study was to measure the objective tumor response rate following treatment with indisulam [E7070; N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide] as second-line therapy in patients with advanced non-small cell lung cancer. The secondary aims were to determine progression-free survival, to assess the safety and tolerability of indisulam, and to study its pharmacokinetic and pharmacodynamic profile.
  
  
  METHODS
  Patients were randomized to receive indisulam every 3 weeks either as a single i.v. dose of 700 mg/m(2) on day one (dx1) or 130 mg/m(2) given on days 1 to 5 inclusive as a daily infusion (dx5). All patients had previously received platinum-based chemotherapy.
  
  
  RESULTS
  Forty-four patients were randomized. Only minor responses were seen. Myelosuppression, gastrointestinal symptoms, and lethargy were the most common toxicities and were more frequent in the dx1 arm. The pharmacokinetics of indisulam in each treatment schedule were adequately described using a previously developed population pharmacokinetic model and were mostly consistent with the results of the phase I program. Flow cytometric analysis of endobronchial and metastatic disease revealed a reduction in the fraction of cycling cells and an increase in apoptosis following indisulam compared with pretreatment levels.
  
  
  CONCLUSIONS
  We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of these treatment schedules has single-agent activity as second-line treatment of non-small cell lung cancer.
authors.affiliation: Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK. denis.talbot@cancer.org.uk
authors.forename: Denis C
authors.initials: DC
authors.lastname: Talbot
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Emma
authors.initials: E
authors.lastname: Cattell
authors.forename: S Murray
authors.initials: SM
authors.lastname: Yule
authors.forename: Claire
authors.initials: C
authors.lastname: Johnston
authors.forename: Anthe S
authors.initials: AS
authors.lastname: Zandvliet
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Norbury
authors.forename: Paul
authors.initials: P
authors.lastname: Ellis
authors.forename: Leon
authors.initials: L
authors.lastname: Bosquee
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides