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

• Authors: Suresh S Ramalingam, Emory University; Shivaani Kummar, Emory University; John Sarantopoulos, Emory University; Stephen Shibata, Emory University; Patricia LoRusso, Emory University; Mara Yerk, Emory University; Julianne Holleran, Emory University; Yan Lin, Emory University; Jan H. Beumer, Emory University; R Donald Harvey, Emory University; S. Percy Ivy, Emory University; Chandra P. Belani, Emory University; Merrill J. Egorin, Emory University
• Journal Title: Journal of Clinical Oncology
• Volume: Volume 28, Number 29
• Publisher: American Society of Clinical Oncology: JCO | 2010-10-10, Pages 4507-4512
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1200/JCO.2010.30.2307
• Subjects: Health Sciences, Oncology; Health Sciences, Rehabilitation and Therapy
• Keywords: lymphomas; cancer; hepatic metastasis; clinical management

Abstract

Purpose 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. Patients and Methods 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. Results 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. Conclusion Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.