The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

• Published in: BMC cancer 2013-05, Vol.13 (1), p.242-242, Article 242
• Main Authors: Rosen, Lee S, Lipton, Lara, Price, Timothy J, Belman, Neil D, Boccia, Ralph V, Hurwitz, Herbert I, Stephenson, Jr, Joe J, Wirth, Lori J, McCoy, Sheryl, Hei, Yong-Jiang, Hsu, Cheng-Pang, Tebbutt, Niall C
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biotechnology industry; Cancer; Cancer therapies; Dosage and administration; Drug dosages; Drug therapy; Female; Gallbladder; Gallbladder - drug effects; Gallbladder - pathology; Gallbladder cancer; Gallbladder diseases; Hospitals; Humans; Hypertension; Indoles - administration & dosage; Indoles - adverse effects; Male; Metastasis; Middle Aged; Neoplasms - drug therapy; Neoplasms - pathology; Niacinamide - administration & dosage; Niacinamide - adverse effects; Niacinamide - analogs & derivatives; Oncology; Pharmaceutical industry; Sludge; Studies; Thrombosis; Ultrasonic imaging; Young Adult
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-13-242

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. 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). 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%. Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. ClinicalTrials.gov NCT00448786.