title: Phase I study of the c-raf-1 antisense oligonucleotide ISIS 5132 in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.
abstract: BACKGROUND
  A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion.
  
  
  RESULTS
  Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum.
  
  
  CONCLUSIONS
  ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. pfidias2@partners.org
authors.forename: Panos
authors.initials: P
authors.lastname: Fidias
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Pennell
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Boral
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Skarin
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
authors.forename: T Jesse
authors.initials: TJ
authors.lastname: Kwoh
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D013873:Thionucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D013873:Thionucleotides; C099587:ISIS 5132; D016190:Carboplatin; D019908:Proto-Oncogene Proteins c-raf; D017239:Paclitaxel