title: The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors.
abstract: BACKGROUND
  Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function.
  
  
  METHODS
  Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment).
  
  
  RESULTS
  Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%.
  
  
  CONCLUSIONS
  Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00448786.
authors.affiliation: Department of Medicine, University of California Los Angeles, Santa Monica, CA, USA. LRosen@mednet.ucla.edu
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Price
authors.forename: Neil D
authors.initials: ND
authors.lastname: Belman
authors.forename: Ralph V
authors.initials: RV
authors.lastname: Boccia
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Joe J
authors.initials: JJ
authors.lastname: Stephenson
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.forename: Sheryl
authors.initials: S
authors.lastname: McCoy
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Hei
authors.forename: Cheng-Pang
authors.initials: CP
authors.lastname: Hsu
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D005704:Gallbladder / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D009841:Oligonucleotides; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; C519562:imetelstat