title: Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer.
abstract: BACKGROUND
  AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models.
  
  
  METHODS
  We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. × 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1).
  
  
  RESULTS
  : One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21).
  
  
  CONCLUSIONS
  The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study.
authors.affiliation: Duke University Medical Center, Durham, NC, USA. neal.ready@duke.edu
authors.forename: Neal
authors.initials: N
authors.lastname: Ready
authors.forename: Nina A
authors.initials: NA
authors.lastname: Karaseva
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Orlov
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Luft
authors.forename: Olexandr
authors.initials: O
authors.lastname: Popovych
authors.forename: Jon T
authors.initials: JT
authors.lastname: Holmlund
authors.forename: Brian A
authors.initials: BA
authors.lastname: Wood
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy* / Q000556:secondary; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D006072:Gossypol; C028178:gossypol acetic acid