Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study.
OBJECTIVE
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.


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.


CONCLUSIONS
Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.
Ramalingam
Suresh S
SS
Emory University, Winship Cancer Institute, Atlanta, GA 30322, USA. Suresh.ramalingam@emory.edu
Kummar
Shivaani
S
Sarantopoulos
John
J
Shibata
Stephen
S
LoRusso
Patricia
P
Yerk
Mara
M
Holleran
Julianne
J
Lin
Yan
Y
Beumer
Jan H
JH
Harvey
R Donald
RD
Ivy
S Percy
SP
Belani
Chandra P
CP
Egorin
Merrill J
MJ
D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000503:physiopathology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D014481:United States; D000077337:Vorinostat
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D000077337:Vorinostat