Document Detail


Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study.
MedLine Citation:
PMID:  20837947     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Suresh S Ramalingam; Shivaani Kummar; John Sarantopoulos; Stephen Shibata; Patricia LoRusso; Mara Yerk; Julianne Holleran; Yan Lin; Jan H Beumer; R Donald Harvey; S Percy Ivy; Chandra P Belani; Merrill J Egorin
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-13
Journal Detail:
Title:  Journal of clinical oncology : official journal of the American Society of Clinical Oncology     Volume:  28     ISSN:  1527-7755     ISO Abbreviation:  J. Clin. Oncol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-08     Completed Date:  2010-10-29     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8309333     Medline TA:  J Clin Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4507-12     Citation Subset:  IM    
Affiliation:
Emory University, Winship Cancer Institute, Atlanta, GA 30322, USA. Suresh.ramalingam@emory.edu
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MeSH Terms
Descriptor/Qualifier:
Anorexia / chemically induced
Antineoplastic Agents / adverse effects,  blood,  pharmacokinetics
Area Under Curve
Diarrhea / chemically induced
Dose-Response Relationship, Drug
Fatigue / chemically induced
Female
Humans
Hydroxamic Acids / adverse effects,  blood,  pharmacokinetics*
Liver / physiopathology*
Male
Metabolic Clearance Rate
Middle Aged
National Cancer Institute (U.S.)
Neoplasms / drug therapy*,  metabolism,  pathology
Thrombocytopenia / chemically induced
Treatment Outcome
United States
Grant Support
ID/Acronym/Agency:
5M01 RR 00056/RR/NCRR NIH HHS; N01 CM-62208/CM/NCI NIH HHS; N01-CO-124001/CO/NCI NIH HHS; P30CA47904/CA/NCI NIH HHS; U01 CA-062487/CA/NCI NIH HHS; U01 CA-062505/CA/NCI NIH HHS; U01-CA099168/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Hydroxamic Acids; 149647-78-9/vorinostat
Comments/Corrections

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