title: A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study.
abstract: BACKGROUND
  Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC.
  
  
  METHODS
  Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0-2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m(2) plus gemcitabine 1000 mg/m(2) intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment.
  
  
  RESULTS
  Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities related to selumetinib were mostly related to oedema and rash, grade 1-2 and manageable. Pharmacokinetic analysis showed that the AUC(0-t), AUC(0-∞) and Cmax of selumetinib increased by 12, 11 and 30 % respectively when it was administered with CisGem, while Cmax for the N-desmethyl metabolite of selumetinib decreased by 40 %. There was no evidence that the time of Cmax for selumetinib or N-desmethyl metabolite of selumetinib were different when selumetinib was administered alone or with CisGem.
  
  
  CONCLUSIONS
  The recommended dose of selumetinib when combined with CisGem was 75 mg bd. Translational studies are underway to identify biomarkers that may predict outcome (ClinicalTrials.gov identifier: NCT01242605 July 6(th) 2010).
authors.affiliation: UCL Cancer Institute, 72 Huntley St, London, WC1E 6DD, UK. j.bridgewater@ucl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Bridgewater
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Andre
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beare
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Marian
authors.initials: M
authors.lastname: Duggan
authors.affiliation: Cancer Research UK and UCL Clinical Trials Centre, London, UK.
authors.forename: Dymphna
authors.initials: D
authors.lastname: Lee
authors.affiliation: UCL Cancer Institute, 72 Huntley St, London, WC1E 6DD, UK.
authors.forename: Maravic
authors.initials: M
authors.lastname: Ricamara
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Delyth
authors.initials: D
authors.lastname: McEntee
authors.affiliation: Imperial College Healthcare, London, UK.
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Sukumaran
authors.affiliation: Imperial College Healthcare, London, UK.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Wasan
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D002423:Cause of Death; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019233:Retreatment; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine