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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00448786.

• Authors: Lee S Rosen, Lara Lipton, Timothy J Price, Neil D Belman, Ralph V Boccia, Herbert I Hurwitz, Joe J Stephenson Jr, Lori J Wirth, Sheryl McCoy, Yong-Jiang Hei, Cheng-Pang Hsu, Niall C Tebbutt
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 242 (May 16 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23679351 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Oligonucleotides
• Niacinamide
• imetelstat

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects)
• Female
• Gallbladder (drug effects, pathology)
• Humans
• Indoles (administration & dosage, adverse effects)
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Niacinamide (administration & dosage, adverse effects, analogs & derivatives)
• Oligonucleotides
• Young Adult