Phase I study of vorinostat for patients with advanced solid tumors and hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI #8057).

Abstract

2545 Background: The histone deacetylase inhibitor, vorinostat, is FDA-approved for treating cutaneous T-cell lymphoma and is being evaluated for treatment of other malignancies. It is metabolized by glucuronidation and b-oxidation. We conducted a phase I study to determine the MTD and PK of vorinostat in patients (pts) with hepatic dysfunction (HD). Methods: Pts had solid malignancies, ECOG PS 0-2, normal bone marrow and renal function. HD was categorized as mild, moderate, or severe by NCI ODWG criteria. 16 pts with normal liver function were enrolled as controls. Initially all patients received a single oral dose of vorinostat (400 mg) followed by extensive PK sampling. After 1 week, vorinostat was given PO QD continuously until progression or toxicity. Vorinostat dose was escalated in sequential cohorts of pts within each HD category. Vorinostat concentrations in plasma were determined with a validated LC-MS/MS method and modeled noncompartmentally. Differences in PK were evaluated using a two-sided Kruskal-Wallis test. Results: 57 pts were enrolled (median age: 57 years, female: 24, PS 0/1: 86%). 41 pts had HD (mild: 15, moderate: 15, severe: 11).The majority of pts had GI malignancies (N=32). 8 of 9 pts who developed dose-limiting toxicity had grade 4 thrombocytopenia. There were no statistically significant differences in vorinostat PK parameters among the normal or HD categories. Disease stabilization was noted in 12 pts. Of 5 pts with adenoid cystic carcinoma, 1 had a PR and 4 had SD. A pt with papillary thyroid cancer has ongoing SD for > 2 years. Conclusions: The recommended doses of vorinostat for pts with mild, moderate, or severe HD are 300 mg, 200 mg, and 100 mg, respectively, on a daily continuous schedule. The PK of vorinostat were not altered by HD and do not explain the differences in recommended doses. Support: NO1 CM-62208 (SEP2C); UO1 CA-99168 (UOP); U01 CA-062505 (CCC); UO1 CA-062487 (Wayne State). HD Cmax(μ M) tmax(h) t1/2(h) AUCINF(μ M*h) ClAPP(l/min) Mean (SD) Normal 1.4 (0.5) 1.4 (0.8) 2.5 (1.2) 5.1 (1.9) 6.4 (5.1) Mild 2.2 (1.1) 2.3 (2.0) 2.0 (1.4) 7.7 (3.4) 4.0 (1.8) Moderate 1.7 (0.6) 2.7 (1.9) 3.5 (2.8) 7.5 (2.4) 3.8 (1.6) Severe 1.8 (0.7) 2.6 (2.2) 2.9 (1.5) 8.3 (5.1) 4.2 (2.3) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck