title: Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma.
abstract: BACKGROUND
  Autophagy is a catabolic pathway that permits cells to recycle intracellular macromolecules, and its inhibition reduces pancreatic cancer growth in model systems. We evaluated hydoxychloroquine (HCQ), an inhibitor of autophagy, in patients with pancreatic cancer and analyzed pharmacodynamic markers in treated patients and mice.
  
  
  METHODS
  Patients with previously treated metastatic pancreatic cancer were administered HCQ at 400 mg (n = 10) or 600 mg (n = 10) twice daily. The primary endpoint was 2-month progression-free survival (PFS). We analyzed peripheral lymphocytes from treated mice to identify pharmacodynamic markers of autophagy inhibition that were then assessed in peripheral lymphocytes from patients.
  
  
  RESULTS
  Among 20 patients enrolled, 2 (10%) were without progressive disease at 2 months. Median PFS and overall survival were 46.5 and 69.0 days, respectively. Treatment-related grade 3/4 adverse events were lymphopenia (n = 1) and elevated alanine aminotransferase (n = 1). Tolerability and efficacy were similar at the two dose levels. Analysis of treated murine lymphocytes suggested that LC3-II expression by Western blot is a reliable marker for autophagy inhibition. Analysis of LC3-II in patient lymphocytes demonstrated inconsistent autophagy inhibition.
  
  
  CONCLUSIONS
  Mouse studies identified LC3-II levels in peripheral lymphocytes as a potential pharmacodynamic marker of autophagy inhibition. In patients with previously treated metastatic pancreatic cancer, HCQ monotherapy achieved inconsistent autophagy inhibition and demonstrated negligible therapeutic efficacy.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA akimmelman@partners.org bwolpin@partners.org.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Rubinson
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: McCleary
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Schrag
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Sikora
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Spicer
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Killion
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Mamon
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Brigham and Women's Hospital, Boston, Massachusetts, USA akimmelman@partners.org bwolpin@partners.org.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D018572:Disease-Free Survival; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D006886:Hydroxychloroquine