title: Phase I trial of vandetanib in combination with gemcitabine and capecitabine in patients with advanced solid tumors with an expanded cohort in pancreatic and biliary cancers.
abstract: BACKGROUND
  Vandetanib is a multitargeted tyrosine kinase inhibitor that affects vascular endothelial growth factor receptor (VEGF), epidermal growth factor (EGF), and rearranged during transfection (RET) mediated receptors which are important for growth and invasion of biliary and pancreatic cancers. This phase I study evaluated the safety profile of vandetanib in combination with standard doses of gemcitabine and capecitabine in order to determine the maximum tolerated dose (MTD).
  
  
  METHODS
  In this single center phase I trial, patients received gemcitabine intravenously (i.v.) at 1000 mg/m2 days 1, 8, 15 in a 28 day cycle, capecitabine orally at 850 mg/m2 twice daily on days 1-21, and escalating doses of vandetanib (200 or 300 mg orally daily). Once the MTD was defined, an expansion cohort of patients with advanced biliary cancers and locally advanced or metastatic pancreatic cancer was enrolled. Blood samples were also collected at predetermined time points for biomarker analysis.
  
  
  RESULTS
  Twenty-three patients were enrolled: 9 in the dose escalation and 14 in the dose expansion cohort. One dose limiting toxicity (DLT), of grade 4 neutropenia, occurred in the 200 mg vandetanib cohort. The most common adverse effects were diarrhea (39 %), nausea and vomiting (34%), and rash (33%). There were 3 partial responses and stable disease of >2 months (range 2-45, median 5) was observed in 15/23 patients. There was no association between changes in biomarker analytes and disease response.
  
  
  CONCLUSIONS
  The combination of gemcitabine, capecitabine and vandetanib is well tolerated at the recommended phase II dose of gemcitabine 1000 mg/m2 weekly for three consecutive weeks, capecitabine 850 mg/m2 BID days 1-21, and vandetanib 300 mg daily, every 28 days. This combination demonstrated promising activity in pancreaticobiliary cancers and further evaluation is warranted in these diseases. NCT00551096.
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Kessler
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.|Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, Aurora, CO, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.affiliation: Department of Clinical Pharmacy, Skaggs School of Pharmacy, Aurora, CO, USA.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'byrant
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Nallapreddy
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Weekes
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Spratlin
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lieu
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA.|University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Madeleine A
authors.initials: MA
authors.lastname: Kane
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Eppers
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Freas
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E 17th Avenue, Room 8120, Aurora, CO, 80045, USA. stephen.leong@ucdenver.edu.|University of Colorado Cancer Center, Aurora, Colorado, USA. stephen.leong@ucdenver.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Leong
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069287:Capecitabine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D010880:Piperidines; D011799:Quinazolines; D003841:Deoxycytidine; D000069287:Capecitabine; C452423:vandetanib; D000093542:Gemcitabine
keywords: Cholangiocarcinoma; EGF; Pancreatic cancer; Phase I; RET; VEGF; Vandetanib