Romidepsin (Depsipeptide, FK228) Induces Clinically Significant Responses in Treatment-Refractory CTCL: Interim Report of a Phase II Multicenter Study.

Background: Romidepsin is a bicyclic peptide which inhibits Class I and II HDACs. An initial study by Piekarz et al noted frequent responses to romidepsin therapy in patients with CTCL (ASCO, 2004). The aim of the pivotal phase II study reported here is to confirm this clinical activity.

Methods: This single arm, open label study is enrolling mycosis fungoides (Stages IB-IVA) or Sezary syndrome patients from 30 centers in the UK, Germany, Poland and the US. Patients with biopsy-proven CTCL (centrally reviewed) that have failed at least one prior systemic therapy receive up to 6 cycles of romidepsin at 14 mg/m2 as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days but may continue therapy if PR or CR is achieved. Eligibility criteria include adequate organ function and ECOG PS less than or equal to 1. Exclusion criteria include significant cardiovascular abnormalities or treatment with QTc-prolonging or CYP3A4-inhibiting drugs.

The primary endpoint is response rate as measured by a combination of imaging, circulating cell counts and a scoring instrument to determine average weighted skin involvement. Skin responses are confirmed by standardized photography. Where possible, correlative studies are performed including acetylation status, apoptotic markers and proteomic analyses. Target accrual is 64 evaluable patients.

Results: 45 patients have received treatment with 31 evaluable for efficacy. Preliminary results of responses are 1 CCR, 11 PRs, 17 SD and 2 PD for an ORR of 39% (duration 3–12 months). One PR became a CCR after more than 6 courses of treatment. In responding patients, time to response ranges from 1–3 cycles. In those patients with pruritus, relief of at least 30 mm from baseline (on a 100 mm VAS) or a VAS score of 0 (no itching) for at least 2 cycles, was seen in 14/26 patients (54%). Seven (7) patients withdrew with PD and 13 for other reasons. Most frequent toxicities are nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. 5 patients have withdrawn for toxicity and there have been no treatment-related deaths.

Conclusions: This study confirms the previously reported efficacy of romidepsin in treatment-refractory CTCL which includes relief of pruritus and a high response rate including one cCR. The low rate of treatment discontinuation due to side-effects and prolonged treatment duration of some patients illustrate that toxicity has been manageable. Accrual continues.