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The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with
Lee S Rosen1, Lara Lipton, Timothy J Price
1Department of Medicine, University of California Los Angeles, Santa Monica, CA, USA. LRosen@mednet.ucla.edu
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.
Trial Registration:
ClinicalTrials.gov NCT00448786.
Insights
Motesanib treatment led to increased gallbladder size and reduced function, with some patients experiencing biliary sludge, gallstones, and cholecystitis. These effects were generally reversible upon stopping the medication.
Area of Science:
- Oncology
- Pharmacology
- Gastroenterology
Background:
- Motesanib, a multi-targeted tyrosine kinase inhibitor, has been associated with gallbladder toxicity.
- Previous reports indicate potential for cholecystitis with motesanib use.
- This study investigates the specific effects of motesanib on gallbladder physiology.
Purpose of the Study:
- To assess the impact of motesanib on gallbladder volume and ejection fraction.
- To evaluate the incidence of gallbladder-related adverse events during motesanib treatment.
- To determine the reversibility of motesanib-induced gallbladder changes.
Main Methods:
- Patients with advanced solid tumors received motesanib at different dosing regimens (125 mg daily or 75 mg BID with varying schedules).
- Gallbladder volume was measured by ultrasound, and ejection fraction was assessed by CCK-HIDA scan.
- Primary endpoints focused on mean changes in gallbladder size and function from baseline.
Main Results:
- Motesanib treatment resulted in a mean increase in gallbladder volume (22.2 cc) and a decrease in ejection fraction (19.2%).
- Adverse events included biliary sludge (up to 39%), gallstone formation (2 patients), and infrequent cholecystitis (3 patients).
- Gallbladder changes were observed across treatment arms and appeared reversible post-discontinuation.
Conclusions:
- Motesanib therapy is linked to significant alterations in gallbladder size and function.
- The drug can induce biliary sludge, gallstone formation, and cholecystitis.
- Observed gallbladder abnormalities generally resolved after motesanib discontinuation.
