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Open Access Research article

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

Lee S Rosen1*, Lara Lipton2, Timothy J Price3, Neil D Belman4, Ralph V Boccia5, Herbert I Hurwitz6, Joe J Stephenson Jr7, Lori J Wirth8, Sheryl McCoy9, Yong-jiang Hei10, Cheng-Pang Hsu11 and Niall C Tebbutt12

Author Affiliations

1 Department of Medicine, University of California Los Angeles, Santa Monica, CA, USA

2 Western Hospital, Footscray, and Royal Melbourne Hospital, Parkville, VIC, Australia

3 The Queen Elizabeth Hospital, University of Adelaide School of Medicine, Woodville, SA, Australia

4 Oncology Hematology of Lehigh Valley, Bethlehem, PA, USA

5 Center for Cancer and Blood Disorders, Bethesda, MD, USA

6 Duke University Medical Center, Durham, NC, USA

7 Cancer Centers of the Carolinas, Greenville, SC, USA

8 Dana-Farber Cancer Institute and Massachusetts General Hospital, Boston, MA, USA

9 Department of Biostatistics, Amgen Inc., South San Francisco, CA, USA

10 Department of Oncology, Amgen Inc., Thousand Oaks, CA, USA

11 Department of Pharmacokinetics & Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA

12 Ludwig Oncology Unit, Austin Hospital, Heidelberg, VIC, Australia

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BMC Cancer 2013, 13:242  doi:10.1186/1471-2407-13-242

Published: 16 May 2013

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