Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study (2008)

Abstract Background: Responses to romidepsin, a novel pan-HDAC inhibitor, have been observed in patients (pts) with cutaneous T-cell Lymphoma (CTCL). This Phase 2B, singlearm, open-label registration study enrolled pts with CTCL (Stages IB–IVA) at 33 European and US sites. Pts with histologically confirmed CTCL who failed ≥1 prior systemic therapy, had adequate organ function, and ECOG PS 0 or 1 were eligible. Exclusions included significant cardiovascular abnormality or treatment with QTc-prolonging or CYP3A4-inhibiting drugs. Pts received romidepsin 14 mg/m2 as a 4-hr IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles (extended for stable disease or response). Aim: The primary endpoint was the response rate among evaluable pts, measured by a combination of a weighted scoring instrument to determine skin involvement (SWAT), imaging, and circulating Sézary cells (as applicable). Results: 96 pts were enrolled and received romidepsin (as-treated); 72 (75%) were evaluable (≥2 cycles) for efficacy. Enrollment is complete, 4 pts with confirmed PR continue to receive romidepsin on extended treatment, 5 pts off-treatment are being followed. Mean age of all pts was 57±12 yrs, and median time since diagnosis was 3 yrs (range &amp;lt;1–26). 68 pts (71%) had disease stage ≥IIB. Median number of prior systemic therapies was 2 (range 1–8). Response (assessed by investigators) and pruritus relief (assessed by visual analog scale [VAS]) data are in the table. Objective disease response rate (ORR) was not lower in pts with advanced-stage disease; 23 (47.9%) of 48 pts with stage IIB-IVA and 7 (29%) of 24 pts with stage IB-IIA achieved OR. With a median follow-up of 5.3 months (mo), median duration of response has not been reached. 50% of responders (evaluable pts) have maintained a response for ≥5 mo and 30% for ≥8 mo. The maximum duration of response was 19.8 mo. 24 (80%) of the 30 pts with a response had not progressed as of the last assessment. Most pts (48/52; 92%) with pruritus at baseline (≥30 mm on VAS) had some relief, including most of those with severe pruritus. Adverse events (AEs) occurred in 93 pts (97%). AEs reported in ≥20% of pts were nausea (56%), asthenia (52%), vomiting (29%), anorexia (23%), hypomagnesemia (21%), and pyrexia (20%). AEs ≥ grade 3 occurred in 32 pts (33%), most commonly fatigue (7%), disease progression (4%), and pyrexia (4%). 21 pts (22%) had a serious AE; the most frequently reported serious AEs were disease progression (6%), pyrexia (3%), sepsis (2%), tumor lysis syndrome (2%), and hypotension (2%). 20 pts (21%) withdrew because of AEs, including fatigue (4%), pyrexia (2%), prolonged QT (2%), and CTCL progression (2%). 6 pts (6%) died, 1 possibly related to treatment. Mean QTcF change from baseline to 2 hrs post-dose was 4.6 msec using baseline assessments before any anti-emetics and 1.3 msec using baseline assessment after anti-emetics. No pts had QTcF values &amp;gt;500 msec. Conclusions: This study shows clinical benefit associated with romidepsin use in treatment-refractory CTCL, with pts achieving durable response and relief from pruritus. Toxicities associated with romidepsin were tolerable and manageable. Evaluable Pts N=72 As-treated Pts N=96 a stable disease for ≥90 days b relief = ≥ 30mm decrease on 100mm VAS or score of 0 for 2 consecutive cycles Confirmed ORR 42% 34% PR, n (%) 24 (33%) 27 (28%) CCR, n (%) 6 (8%) 6 (6%) SD90a, n (%) 26 (36%) 28 (29%) Overall disease control (CCR+PR+SD90) 56 (78%) 61 (64%) Median time (mo) to response (range) 1.9 (0.9–4.8) 1.9 (0.9–4.8) Median time (mo) to disease progression (range) 9.0 (2.7–21.7) 8.3 (0–21.7) Confirmed OR in stage ≥ IIB, n (%) 23/48 (48%) 26/68 (38%) Relief of pruritusb, n (%) 25/52 (48%) NA Relief of severe pruritus, n (%) 16/29 (55%) NA