A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction
Year: 2019
Type: article
Study design: Clinical Trial
Abstract: Aims The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results Seventy‐two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m2/day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
DOI: 10.1111/bcp.14054
Authors: Naoko Takebe, Jan H. Beumer, Shivaani Kummar, Brian F. Kiesel, Afshin Dowlati, Geraldine O'Sullivan Coyne, Richard Piekarz, Lawrence Rubinstein, Laura K. Fogli, Ulka Vaishampayan, Sanjay Goel, Cindy L. O'Bryant, Bassel F. El‐Rayes, Vincent Chung, Heinz‐Josef Lenz, Richard Kim, Chandra P. Belani, Joseph M. Tuscano, William Schelman, Nancy Moore, James H. Doroshow, Alice P. Chen
Institutions: National Institutes of Health, National Cancer Institute, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, University Hospitals Seidman Cancer Center, Case Western Reserve University, Wayne State University, The Barbara Ann Karmanos Cancer Institute, Albert Einstein College of Medicine, Montefiore Medical Center, University of Colorado Cancer Center, Winship Cancer Institute, City Of Hope National Medical Center, City of Hope, University of Southern California, USC Norris Comprehensive Cancer Center, Moffitt Cancer Center, Penn State Cancer Institute, Penn State Milton S. Hershey Medical Center, University of California Davis Medical Center, UC Davis Comprehensive Cancer Center, University of Wisconsin–Madison, University of Wisconsin Carbone Cancer Center, Center for Cancer Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Awards: G1529121756, Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis, G329278553, G3503792436, G3565137481, G386607036, G422284981, G424558205, G4585269469, G5888954722, G6819179691, G72906764, G741073515, NCI ETCTN Pittsburgh Cancer Consortium (PCC), Phase 1 and 2 Molecular and Clinical Pharmacodynamic Trials ETCTN, Southern California Clinical and Translational Science Institute, CANCER CENTER SUPPORT GRANT
OpenAlex ID: W2954589048