Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Clinical Benefit to Advanced Cutaneous T-Cell Lymphoma Patients: Updated Results of the Phase IIb Multicenter Clinical Trial. (2006)

Abstract Purpose: To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat in advanced cutaneous T-cell lymphoma (CTCL) patients (pts). Patients and Methods: Advanced CTCL pts received oral vorinostat 400 mg daily until disease progression (PD) or intolerable toxicity in this open label Phase IIb trial. Eligible pts must have received ≥ 2 prior systemic therapies which included bexarotene unless intolerable. The planned sample size was ≥ 50 evaluable pts with stage ≥ IIB. The primary endpoint was the objective response rate (ORR) as measured by a modified skin severity weighted assessment tool (SWAT). The study would be positive if the ORR in ≥ stage IIB pts was ≥ 20%. Time to response, time to progression (TTP), response duration (DOR, from time of first response), pruritus relief, safety and gene expression changes were also evaluated. Results: Seventy-four pts (median age, 60 y [range, 39–83]; median 3 prior systemic therapies) were enrolled (61 pts ≥ stage IIB) at 18 centers. Data cut-off was 5/06 with a median follow-up of 10 m. Efficacy data are shown (Table 1). The ORR was 29.5% in ≥ stage IIB pts. The median DOR and TTP were not reached but estimated to be at least 6.1 m and 9.8 m, respectively, for ≥ stage IIB responders. Median TTP was 4.9 m for all pts. Overall, 32% of pts had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%) and anorexia (26%), and were mostly ≤ grade 2. Seven pts discontinued and 10 had dose modification due to drug-related AE. Drug-related AE ≥ grade 3 included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%) and nausea (4%). Fifteen pts, including 9 responders, were receiving treatment as of 11/05. Three of these pts discontinued due to PD (n = 2) or unacceptable toxicity (n = 1), and 12 have received vorinostat for &amp;gt; 1 y. A pharmacodynamic signature of vorinostat exposure based on gene expression changes was detected. Conclusion: These updated results with additional follow-up continue to demonstrate that oral vorinostat remains effective in advanced CTCL with an acceptable safety profile. Table 1. Efficacy of Vorinostat in Advanced CTCL Population n Objective Response* Median (range) n Pruritus Relief† *Objective response = confirmed complete or partial response. †Sustained pruritus reduction of ≥ 3 points or complete resolution for ≥ 4 wks; 2 pts with missing baseline scores were excluded. ‡Kaplan-Meier estimates were not reached but DOR was ≥ 165, 185 and 165 d, respectively, with a median follow-up of 10 m. §Stages IIB, III, IVA or IVB. CI = confidence interval n (%) (95% CI) TTR, d DOR, d n (%; 95% CI) All pts 74 22 (29.7) (19.7, 41.5) 55 (28–171) NR‡ (34+, 441+) 72 23 (31.9; 21.4, 44.0) Stage IB or IIA 13 4 (30.8) (9.1, 61.4) 42.5 (30–57) 80.5 (48+, 418+) 13 5 (38.5; 13.9, 68.4) ≥Stage IIB§ 61 18 (29.5) (18.5, 42.6) 56 (28–171) NR‡ (34+, 441+) 59 18 (30.5; 19.2, 43.9) Sezary syndrome 30 10 (33.3) (17.3, 52.8) 56 (28–171) NR‡ (34+, 244+) 30 9 (30.0; 14.7, 49.4)