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 head and neck squamous cell cancer.
abstract: BACKGROUND
  The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. 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 HNSCC.
  
  
  METHODS
  Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75mg/m(2) IV every 21days) with or without PX-866 (8mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes.
  
  
  RESULTS
  85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P=0.13). Median PFS was 92days in Arm A and 82days in Arm B (P=0.42). There was no difference in OS between the two arms (263 vs. 195days; P=0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed.
  
  
  CONCLUSIONS
  The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.
authors.affiliation: University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: antonio.jimeno@ucdenver.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Bauman
authors.affiliation: New York Hematology, New York, NY, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Weissman
authors.affiliation: Washington University, St. Louis, MO, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Adkins
authors.affiliation: Compass Oncology, Tualatin, OR, United States; US Oncology Research, The Woodlands, TX, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Schnadig
authors.affiliation: CHUS Hôpital Fleurimont, Quebec, Canada.
authors.forename: Patrice
authors.initials: P
authors.lastname: Beauregard
authors.affiliation: University of Colorado School of Medicine, Aurora, CO, United States; Denver Veterans Affairs Medical Center, Denver, CO, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
authors.affiliation: Virginia Cancer Specialists, Fairfax, VA, United States; US Oncology Research, The Woodlands, TX, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Spira
authors.affiliation: Beth Israel Hospital, St. Luke's Hospital, Mount Sinai Health System, New York, NY, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levy
authors.affiliation: New York University, New York, NY, United States.
authors.forename: Nagashree
authors.initials: N
authors.lastname: Seetharamu
authors.affiliation: Oncothyreon Inc., Seattle, WA, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Hausman
authors.affiliation: Oncothyreon Inc., Seattle, WA, United States.
authors.forename: Luke
authors.initials: L
authors.lastname: Walker
authors.affiliation: Johns Hopkins University, Baltimore, MD, United States.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shirai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D000077143:Docetaxel; D005260:Female; D006067:Gonanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012008:Recurrence; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel
keywords: Docetaxel; Head and neck squamous cell cancer; PI3K; PIK3CA