Simon R. were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. Conclusion The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable Losartan responses in patients with CTCL. INTRODUCTION Histone deacetylase inhibitors (HDIs) cause growth arrest, cellular differentiation, and apoptosis.1C4 Their antitumor effects have been hypothesized to occur through modulation of gene expression; however, Losartan acetylation of nonhistone proteins may be more important.5,6 Romidepsin (FK228, “type”:”entrez-nucleotide”,”attrs”:”text”:”FR901228″,”term_id”:”525229482″FR901228, depsipeptide), (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methyletheyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone, is a potent HDI isolated from (Appendix Fig A1, online only).7,8 Dramatic responses observed in patients with T-cell lymphoma9C11 prompted a phase II trial to assess the response rate and toxicity profile. The activity of romidepsin Losartan in cutaneous T-cell lymphoma (CTCL) seems to be a class effect, with other HDIs also found to demonstrate activity.12,13 Between 2,000 and 3,000 new cases of CTCL occur in the United States Losartan each year, with mycosis fungoides (MF) and the Szary syndrome (SS) being the predominant subtypes.14 MF is categorized as limited stage (IA, IB, and IIA), characterized as plaques or patches limited to skin, and advanced stage (IIB to IVB), characterized by cutaneous tumors and involvement of the blood, lymph nodes, bone marrow, or visceral organs.15 SS is characterized by generalized erythroderma and abnormal lymphoid cells in the blood.16 Limited-stage disease may effectively be treated with skin-directed therapies including topical nitrogen mustard or psoralen plus ultraviolet A therapy.17 However, in patients with advanced disease, control is often short lived, and the disease is relentlessly progressive. Although response rates to cytotoxic chemotherapy range from 60% to 80% in patients with advanced disease, the median duration of response is usually measured in months.18 Agents with novel mechanisms of action have been pursued, including retinoids, interferon, monoclonal antibodies, and denileukin diftitox; none has been found to be curative. This trial was initiated to evaluate the efficacy of romidepsin in patients with T-cell lymphoma. Secondary goals included evaluation of long-term safety of romidepsin. This report is limited to patients with MF or SS; patients with peripheral T-cell lymphoma (PTCL) will be reported separately. PATIENTS AND METHODS Patient Eligibility Patients with relapsed, refractory, or advanced CTCL, either as MF or SS, were eligible. The first cohort included patients who had received no more than two systemic cytotoxic chemotherapy regimens. Topical therapies, such as psoralen plus ultraviolet A therapy or topical chemotherapy; systemic therapies, such as corticosteroids, retinoids, interferon, or denileukin diftitox; and nonradiolabeled antibodies, such as alemtuzumab, were not considered cytotoxic chemotherapy; prior therapy with any number of these therapies was allowed. Patients with stage IA, IB, or IIA disease15 were only eligible if they were refractory to, intolerant of, or had reached a 6-month or longer response plateau on at least two prior CTCL therapies. The observed activity led us to open the trial at additional sites and to include patients who had previously received more than two cytotoxic therapies. In addition, after completion of the first cohort, a replicate cohort with the same inclusion criteria was undertaken. The protocol, informed consent, and subsequent amendments were approved by the institutional Losartan review Rabbit Polyclonal to ARSE boards of all participating institutions..