title: A multicenter phase 1 study of PX-866 and cetuximab in patients with metastatic colorectal carcinoma or recurrent/metastatic squamous cell carcinoma of the head and neck.
abstract: BACKGROUND
  This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck.
  
  
  METHODS
  PX-866 was administered at escalating doses (6-8 mg daily) combined with cetuximab given at a 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly. A "3 + 3" study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed.
  
  
  RESULTS
  Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1%), followed by hypomagnesemia (72.2%), vomiting (72.2%), fatigue (54.5%), nausea (54.5%), rash (45.5%) and peripheral edema (40%). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4%), 4 stable disease (44.4%), and 1 disease progression (11.1%). The median progression free survival was 106 days (range: 1-271).
  
  
  CONCLUSIONS
  Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, 12801 East 17th Avenue MS 8117 Aurora, Denver, CO, 80045, USA, daniel.bowles@ucdenver.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: Diana
authors.initials: D
authors.lastname: Hausman
authors.forename: Scott
authors.initials: S
authors.lastname: Peterson
authors.forename: Alex
authors.initials: A
authors.lastname: Vo
authors.forename: Luke
authors.initials: L
authors.lastname: Walker
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006067:Gonanes / Q000008:administration & dosage / Q000009:adverse effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D066066:Response Evaluation Criteria in Solid Tumors; D000077195:Squamous Cell Carcinoma of Head and Neck; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D006067:Gonanes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C117307:KRAS protein, human; C496788:PX-866; C484760:PIK3CA protein, human