Phase I Study of Vorinostat in Patients With Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

DOI Web Site 被引用文献2件
  • Suresh S. Ramalingam
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Shivaani Kummar
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • John Sarantopoulos
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Stephen Shibata
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Patricia LoRusso
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Mara Yerk
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Julianne Holleran
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Yan Lin
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Jan H. Beumer
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • R. Donald Harvey
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • S. Percy Ivy
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Chandra P. Belani
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.
  • Merrill J. Egorin
    From Emory University, Atlanta, GA; National Cancer Institute, Bethesda; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD; Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX; City of Hope Cancer Center, Duarte, CA; Karmanos Cancer Institute, Detroit, MI; University of Pittsburgh Cancer Institute, Pittsburgh; and Penn State Hershey Cancer Institute, Hershey, PA.

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<jats:sec><jats:title>Purpose</jats:title><jats:p> Vorinostat is the first US Food and Drug Administration–approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography–tandem mass spectrometry assay and modeled noncompartmentally. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered. </jats:p></jats:sec>

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