title: A phase 2 study of oral MKC-1, an inhibitor of importin-β, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer.
abstract: BACKGROUND
  MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer.
  
  
  METHODS
  Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100 mg/m(2) dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150 mg per day.
  
  
  RESULTS
  20 of an original target of 33 patients were accrued, with a median age of 61 (range 44-81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia.
  
  
  CONCLUSIONS
  MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.
authors.affiliation: Department of Medical Oncology, Massachusetts General Hospital Cancer Center, POB 221, Boston, MA 02114, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Faris
authors.forename: Jamie
authors.initials: J
authors.lastname: Arnott
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Blaszkowsky
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wolpin
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003710:Demography; D018450:Disease Progression; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism*; D028961:beta Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D014404:Tubulin; D028961:beta Karyopherins; C488881:1H-pyrrole-2,5-dione, 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases