title: A dose escalation study of gemcitabine plus oxaliplatin in combination with imatinib for gemcitabine-refractory advanced pancreatic adenocarcinoma.
abstract: BACKGROUND
  Targeting platelet-derived growth factor receptor-β (PDGFR-β) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-β inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC).
  
  
  METHODS
  Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2-5) each cycle.
  
  
  RESULTS
  Twenty-seven patients received 168 cycles in total. Median age was 61 years (44-74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1-7.0) and 5.6 months (95% CI 2.5-8.7), respectively.
  
  
  CONCLUSIONS
  In gemcitabine-refractory PC, gemcitabine (1000 mg/m(2)) and oxaliplatin (85 mg/m(2)) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.
authors.affiliation: Department of Medicine,Royal Marsden Hospital, NHS Foundation Trust, Surrey and London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Starling
authors.forename: E A
authors.initials: EA
authors.lastname: Hawkes
authors.forename: I
authors.initials: I
authors.lastname: Chau
authors.forename: D
authors.initials: D
authors.lastname: Watkins
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.forename: J
authors.initials: J
authors.lastname: Webb
authors.forename: G
authors.initials: G
authors.lastname: Brown
authors.forename: K
authors.initials: K
authors.lastname: Thomas
authors.forename: Y
authors.initials: Y
authors.lastname: Barbachano
authors.forename: J
authors.initials: J
authors.lastname: Oates
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D009944:Organoplatinum Compounds; D010879:Piperazines; D011743:Pyrimidines; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; D000093542:Gemcitabine