A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction

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 Belani, Joseph M. Tuscano, William Schelman, Nancy MooreJames H. Doroshow, Alice P. Chen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBritish Journal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2019

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Liver Diseases
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Liver
belinostat
Safety
Histone Deacetylase Inhibitors
Metabolic Networks and Pathways
Pharmaceutical Preparations
Guidelines

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Takebe, N., Beumer, J. H., Kummar, S., Kiesel, B. F., Dowlati, A., O'Sullivan Coyne, G., ... Chen, A. P. (Accepted/In press). A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction. British Journal of Clinical Pharmacology. https://doi.org/10.1111/bcp.14054
Takebe, Naoko ; Beumer, Jan H. ; Kummar, Shivaani ; Kiesel, Brian F. ; Dowlati, Afshin ; O'Sullivan Coyne, Geraldine ; Piekarz, Richard ; Rubinstein, Lawrence ; Fogli, Laura K. ; Vaishampayan, Ulka ; Goel, Sanjay ; O'Bryant, Cindy L. ; El-Rayes, Bassel F. ; Chung, Vincent ; Lenz, Heinz Josef ; Kim, Richard ; Belani, Chandra ; Tuscano, Joseph M. ; Schelman, William ; Moore, Nancy ; Doroshow, James H. ; Chen, Alice P. / A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction. In: British Journal of Clinical Pharmacology. 2019.
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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.",
author = "Naoko Takebe and Beumer, {Jan H.} and Shivaani Kummar and Kiesel, {Brian F.} and Afshin Dowlati and {O'Sullivan Coyne}, Geraldine and Richard Piekarz and Lawrence Rubinstein and Fogli, {Laura K.} and Ulka Vaishampayan and Sanjay Goel and O'Bryant, {Cindy L.} and El-Rayes, {Bassel F.} and Vincent Chung and Lenz, {Heinz Josef} and Richard Kim and Chandra Belani and Tuscano, {Joseph M.} and William Schelman and Nancy Moore and Doroshow, {James H.} and Chen, {Alice P.}",
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Takebe, N, Beumer, JH, Kummar, S, Kiesel, BF, Dowlati, A, O'Sullivan Coyne, G, Piekarz, R, Rubinstein, L, Fogli, LK, Vaishampayan, U, Goel, S, O'Bryant, CL, El-Rayes, BF, Chung, V, Lenz, HJ, Kim, R, Belani, C, Tuscano, JM, Schelman, W, Moore, N, Doroshow, JH & Chen, AP 2019, 'A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction', British Journal of Clinical Pharmacology. https://doi.org/10.1111/bcp.14054

A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction. / Takebe, Naoko; Beumer, Jan H.; Kummar, Shivaani; Kiesel, Brian F.; Dowlati, Afshin; O'Sullivan Coyne, Geraldine; Piekarz, Richard; Rubinstein, Lawrence; Fogli, Laura K.; Vaishampayan, Ulka; Goel, Sanjay; O'Bryant, Cindy L.; El-Rayes, Bassel F.; Chung, Vincent; Lenz, Heinz Josef; Kim, Richard; Belani, Chandra; Tuscano, Joseph M.; Schelman, William; Moore, Nancy; Doroshow, James H.; Chen, Alice P.

In: British Journal of Clinical Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - A phase I pharmacokinetic study of belinostat in patients with advanced cancers and varying degrees of liver dysfunction

AU - Takebe, Naoko

AU - Beumer, Jan H.

AU - Kummar, Shivaani

AU - Kiesel, Brian F.

AU - Dowlati, Afshin

AU - O'Sullivan Coyne, Geraldine

AU - Piekarz, Richard

AU - Rubinstein, Lawrence

AU - Fogli, Laura K.

AU - Vaishampayan, Ulka

AU - Goel, Sanjay

AU - O'Bryant, Cindy L.

AU - El-Rayes, Bassel F.

AU - Chung, Vincent

AU - Lenz, Heinz Josef

AU - Kim, Richard

AU - Belani, Chandra

AU - Tuscano, Joseph M.

AU - Schelman, William

AU - Moore, Nancy

AU - Doroshow, James H.

AU - Chen, Alice P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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