title: A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer.
abstract: OBJECTIVE
  This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer.
  
  
  METHODS
  Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2.
  
  
  RESULTS
  Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients.
  
  
  CONCLUSIONS
  Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.
authors.affiliation: Division of Medical Oncology and Hematology, Rm 5-708, Princess Margaret Hospital, 610 University Avenue, Toronto M5G2M9, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Renouf
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.forename: David
authors.initials: D
authors.lastname: Hedley
authors.forename: Sharlene
authors.initials: S
authors.lastname: Gill
authors.forename: Derek
authors.initials: D
authors.lastname: Jonker
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Walde
authors.forename: Rakesh
authors.initials: R
authors.lastname: Goel
authors.forename: Bernadette
authors.initials: B
authors.lastname: Southwood
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gauthier
authors.forename: Wendy
authors.initials: W
authors.lastname: Walsh
authors.forename: Lynn
authors.initials: L
authors.lastname: McIntosh
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000008:administration & dosage; D002170:Canada; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003841:Deoxycytidine; C515233:saracatinib; D019061:src-Family Kinases; D000093542:Gemcitabine