ST LOUIS (MD Consult) - On November 5, 2009, Gloucester Pharmaceuticals announced that the US Food and Drug Administration approved Istodax (romidepsin) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have previously received at least 1 form of systemic therapy. Istodex is a member of a new class of cancer drugs known as histone deacetylase inhibitors. CTCL is a type of non-Hodgkin’s lymphoma.
The Istodax approval was granted on the basis of data from 2 prospective, multicenter, single-arm clinical studies that involved patients with CTCL. The efficacy of Istodax was evaluated in 167 patients from the United States, Europe, and Australia. The first study (study 1), which was sponsored by Gloucester, included 96 patients with confirmed CTCL whose condition had failed to respond to at least 1 course of systemic therapy. The second study (study 2), which was sponsored by the National Cancer Institute, included 71 patients with a primary diagnosis of CTCL who had previously received at least 2 skin-directed therapies or 1 or more systemic therapies. The patients were treated with Istodax at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.
In both studies, patients could continue treatment until disease progression, at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite end point that included assessments of skin, lymph node, and visceral involvement and abnormal circulating T-cells (ie, Sézary cells).
The primary efficacy end point for both studies was overall objective disease response rate (ORR) as determined by investigator assessments and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). Complete response was defined as no evidence of disease, and partial response was defined as ≥50% improvement in disease. Secondary end points in both studies included duration of response and time to response.
The ORRs in the trials were similar (34% and 35% in study 1 and study 2, respectively) and CR rates were the same (6%). The median response duration was 15 months (range, 1 to 20+ months) in study 1 and 11 months (range, 1 to 66+ months) in study 2. Median time to first response was 2 months (range, 1-6 months) in both studies. Median time to CR was 6 months in Study 1 and 4 months in study 2 (range, 2-9 months).
The most common adverse reactions reported in study 1 were nausea, fatigue, infection, vomiting, and anorexia and in study 2 were nausea, fatigue, anemia, thrombocytopenia, neutropenia, lymphopenia, and electrocardiographic T-wave changes. Most of the adverse reactions were classified as mild or moderate in severity. Most deaths in the studies occurred as the result of disease progression.
Istodax is expected to be commercially available in January 2010.
圣路易斯(MD Consult)——2009年11月5日，Gloucester制药公司宣布，美国食品药品管理局(FDA)批准Istodax(romidepsin)作为皮肤T细胞淋巴瘤(CTCL)治疗药用于治疗先前曾接受过至少1种系统治疗的患者。Istodex是名为组蛋白去乙酰化酶抑制剂的一类抗癌新药成员。CTCL是一种非霍奇金淋巴瘤。
Istodax的获准是基于对CTCL患者进行的两项前瞻性、多中心、单组临床研究的数据。Istodax的有效性评估在美国、欧洲和澳大利亚的167例患者中展开。第1项研究(研究1)得到了Gloucester公司的资助，共纳入96例CTCL确诊患者，这些患者对至少1个疗程的系统治疗无效。第2项研究(研究2)得到了国家癌症研究所的资助，共纳入71例初步诊断为CTCL、先前曾接受过至少2种皮肤靶向治疗或1种以上(包括1种)系统治疗的患者。这些患者的Istodax初始剂量为14 mg/m2，疗程为28 d，在每个疗程的第1、8及15 d用药。
在这两项研究中，根据研究者和当地监管部门的判断，患者可在病情进展前继续用药。根据包括皮肤、淋巴结及内脏受累情况和循环中异常T细胞(即评价的复合终点)对客观疗效进行评估。
两项研究的主要有效性终点为整体客观有效率(ORR)，通告研究者评估判定，定义为确定完全有效(CR)或部分有效(PR)的患者比例。完全有效定义为无疾病证据，部分有效定义为病情获得至少50%的改善。两项研究的次要终点均为疗效持续时间和起效时间。
两项研究的ORR相近(在研究1与研究2中分别为34%和35%)，CR相同(均为6%)。在中位疗效持续时间上，研究1为15个月(范围，1至20个月以上)，研究2为11个月(范围，1至66个月以上)。研究1和研究2中中位至CR时间分别为6个月和4个月(范围，2~9个月)。
研究1中报告的最常见的不良反应为恶心、疲劳、感染、呕吐、食欲减退，研究2中为恶心、疲劳、贫血、血小板减少、中性粒细胞减少、淋巴细胞减少以及心电图T波改变。大多数不良反应属于轻至中度。研究中大多数死亡系病情恶化所致。
预计Istodax将于2010年1月上市。
