title: A phase I/II, non-randomized, feasibility/safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer.
abstract: BACKGROUND
  Improvements in knowledge of molecular mechanisms in cancer are the basis for new studies combining chemotherapy with targeted drugs. Inhibition of the epidermal growth factor receptor (EGFR) by erlotinib or cetuximab has limited or no activity, respectively, in pancreatic cancer. The crosstalk between EGFR and mammalian target of rapamycin (mTOR) pathways is a potential mechanism of resistance; therefore we conducted a study to explore safety and efficacy of multiple pathway inhibition by cetuximab and everolimus in combination with capecitabine.
  
  
  METHODS
  Safety and efficacy of fixed standard dose cetuximab in combination with various dose levels of everolimus (5-10 mg/day) and capecitabine (600-800 mg/m(2) bid, 2 weeks every 3 weeks) were investigated in a phase I/II study in patients with advanced pancreatic cancer. The primary endpoint was objective response.
  
  
  RESULTS
  Sixteen patients were treated in the phase I part at two dose levels. Mucositis, rash and hand-foot syndrome were dose-limiting toxicities. Dose level 1 (everolimus 5 mg/day, capecitabine 600 mg/m(2) bid for 2 weeks every 3 weeks and cetuximab 250 mg/m(2) weekly) was considered the maximum tolerated dose (MTD). Of 31 patients in the phase II part, partial response was documented in two patients (6.5%) and five (16.1%) had stable disease. Median overall survival was 5.0 months (CI 3.1-6.8).
  
  
  CONCLUSIONS
  The schedule of capecitabine, everolimus and cetuximab resulted in considerable epidermal and mucosal toxicities and prevented escalation to optimal dose levels. Because of toxicity and low efficacy this treatment combination cannot be recommended for treatment in pancreatic cancer patients.
authors.affiliation: Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. s.kordes@amc.uva.nl
authors.forename: Sil
authors.initials: S
authors.lastname: Kordes
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Klümpen
authors.forename: Mariëtte J
authors.initials: MJ
authors.lastname: Weterman
authors.forename: Arnoldus J W M
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Wilmink
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000069287:Capecitabine; D000068818:Cetuximab; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000068338:Everolimus; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D000068338:Everolimus; D000068818:Cetuximab; D005472:Fluorouracil; D020123:Sirolimus