title: A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer.
abstract: BACKGROUND
  The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non-small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC.
  
  
  METHODS
  Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes.
  
  
  RESULTS
  A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed.
  
  
  CONCLUSIONS
  The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.
authors.affiliation: Beth Israel Hospital, St. Luke's Hospital, Mount Sinai Health System, New York, New York. Electronic address: belevy@chpnet.org.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levy
authors.affiliation: Virginia Cancer Specialists, Fairfax, Virginia; US Oncology Research, The Woodlands, Texas.
authors.forename: Alexander
authors.initials: A
authors.lastname: Spira
authors.affiliation: Beth Israel Hospital, St. Luke's Hospital, Mount Sinai Health System, New York, New York.
authors.forename: Daniel
authors.initials: D
authors.lastname: Becker
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Tracey
authors.initials: T
authors.lastname: Evans
authors.affiliation: US Oncology Research, The Woodlands, Texas; Northwest Cancer Specialists, Portland, Oregon.
authors.forename: Ian
authors.initials: I
authors.lastname: Schnadig
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: Oncothyreon Inc., Seattle, Washington.
authors.forename: Diana
authors.initials: D
authors.lastname: Hausman
authors.affiliation: Oncothyreon Inc., Seattle, Washington.
authors.forename: Luke
authors.initials: L
authors.lastname: Walker
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.affiliation: Johns Hopkins University, Baltimore, Maryland; Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado; Section of Hematology/Oncology, Denver Veterans Affairs Medical Center, Denver, Colorado.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006067:Gonanes / Q000008:administration & dosage; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D000077143:Docetaxel; D006067:Gonanes; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043823:Taxoids; C496788:PX-866; C484760:PIK3CA protein, human; C494929:PTEN protein, human