title: Phase II trial of gemcitabine and tanespimycin (17AAG) in metastatic pancreatic cancer: a Mayo Clinic Phase II Consortium study.
abstract: OBJECTIVE
  Heat Shock Protein 90 (HSP90) is a molecular chaperone that stabilizes many oncogenic proteins. HSP90 inhibitors may sensitize tumors to cytotoxic agents by causing client protein degradation. Gemcitabine, which has modest activity in pancreas cancer, activates Chk1, a client protein of HSP90. This phase II trial was designed to determine whether 17AAG could enhance the clinical activity of gemcitabine through degradation of Chk1 in patients with stage IV pancreatic cancer.
  
  
  METHODS
  A multicenter, prospective study combining gemcitabine and 17AAG enrolled patients with stage IV pancreatic adenocarcinoma, adequate liver and kidney function, ECOG performance status 0-2, and no prior chemotherapy for metastatic disease. The primary goal was to achieve a 60 % overall survival at 6 months. Sixty-six patients were planned for accrual, with an interim analysis after 25 patients enrolled.
  
  
  RESULTS
  After a futility analysis to achieve the endpoint, accrual was halted with 21 patients enrolled. No complete or partial responses were seen. Forty percent of patients were alive at 6 months. Median overall survival was 5.4 months. Tolerability was moderate, with 65 % of patients having ≥ grade 3 adverse events (AE), and 15 % having grade 4 events.
  
  
  CONCLUSIONS
  The lack of clinical activity suggests that targeting Chk1 by inhibiting HSP90 is not important in pancreatic cancer sensitivity to gemcitabine alone. Further studies of HSP90 targeted agents with gemcitabine alone are not warranted.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA, pedersen.katrina@mayo.edu.
authors.forename: Katrina S
authors.initials: KS
authors.lastname: Pedersen
authors.forename: George P
authors.initials: GP
authors.lastname: Kim
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C112765:tanespimycin; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine