title: Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Clusterin (CLU), an antiapoptotic, stress-associated protein, confers resistance to therapy when overexpressed. This trial tested custirsen (OGX-011), an inhibitor of CLU protein production, combined with gemcitabine/platinum in patients with advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  This was a single-arm, multicenter, phase I/II study in chemotherapy-naive stage IIIB/IV NSCLC. Custirsen was infused during a loading dose period and weekly in combination with gemcitabine (1250 mg/m) on days 1 and 8 and with cisplatin (75 mg/m) or carboplatin (area under the curve 5) on day 1 of each 21-day cycle. Ten patients were treated in a phase I lead-in and 71 in the phase II component. The primary efficacy endpoint was response rate, with exploratory analyses of other efficacy outcomes and biomarker relationships.
  
  
  RESULTS
  Eighty-one patients received custirsen and were included in the primary analysis. The median age was 61 years; 82% had stage IV disease. Overall response was 25 of 81 (31%; 95% confidence interval 21-42). The 1- and 2-year survivals were 54 and 30%, respectively. Toxicity of the combination was not appreciably different from what is reported for gemcitabine/platinum combinations. Custirsen treatment decreased serum CLU levels in 95% of patients evaluated. Patients who achieved a minimum median CLU level for the population of ≤38 μg/ml during treatment had a median survival of 27.1 compared with 16.1 months for patients who did not (p = 0.02).
  
  
  CONCLUSIONS
  Based on the above results, a randomized phase 3 trial to evaluate the survival benefit of custirsen in patients with NSCLC is warranted.
authors.affiliation: BC Cancer Centre, Vancouver, British Columbia, Canada. jlaskin@bccancer.bc.ca
authors.forename: Janessa J
authors.initials: JJ
authors.lastname: Laskin
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholas
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee
authors.forename: Barbara
authors.initials: B
authors.lastname: Gitlitz
authors.forename: Mark
authors.initials: M
authors.lastname: Vincent
authors.forename: Yvon
authors.initials: Y
authors.lastname: Cormier
authors.forename: Joe
authors.initials: J
authors.lastname: Stephenson
authors.forename: Yee
authors.initials: Y
authors.lastname: Ung
authors.forename: Rachel
authors.initials: R
authors.lastname: Sanborn
authors.forename: Bryn
authors.initials: B
authors.lastname: Pressnail
authors.forename: Francis
authors.initials: F
authors.lastname: Nugent
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Nevin
authors.initials: N
authors.lastname: Murray
authors.forename: Desiree
authors.initials: D
authors.lastname: Hao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D015996:Survival Rate; D013873:Thionucleotides / Q000627:therapeutic use*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: C503781:OGX-011; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D003841:Deoxycytidine; D016190:Carboplatin; D002945:Cisplatin; D000093542:Gemcitabine