2009年11月9日,美国食品药品监督管理局（FDA）批准注射药物Istodax （romidepsin）用于治疗一种名为皮肤T细胞淋巴瘤（CTCL）的罕见癌症。
 
皮肤T细胞淋巴瘤是一种名为T-淋巴细胞的抗感染白细胞缓慢生长的癌症。大多数病例在开始时伴有皮肤干燥、红疹和瘙痒，并可能加重。可能发生肿瘤的皮肤会出现溃疡并引发感染。在一些病例中，CTCL可扩散至血液、淋巴结或内部器官。在美国，每年约有1500个新的CTCL病例。伴有皮肤局部CTCL的患者可接受局部药物或光疗治疗，一旦病情恶化，则可能需要进行化疗。
 
Istodax可干扰细胞复制程序。该药被计划用于在已使用至少一种其他类型的化疗后病情仍趋于恶化或复发的CTCL患者。FDA药物评估和研究中心的肿瘤药品办公室主任Richard Pazdur博士表示，“这次批准证明了FDA有关发展和批准用于治疗罕见和少见疾病药物的承诺。”FDA于2009年11月6日批准Istodax上市。之前已批准用于治疗CTCL的药物包括Zolinza （vorinostat）、Ontak （denileukin difitox）和Targretin （bexarotene）。
 
Istodax的评估是基于2项共纳入167名患者的临床研究。在这 2项试验中约有35%的患者出现治疗反应，表现为肿瘤的大小减小。在其中1项研究中，治疗反应的持续中位时间为15个月，另一项研究为11个月。研究中有 6%的患者已完成治疗，并通过体格、实验室和X-射线检查未发现肿瘤迹象。

常见副作用包括恶心、疲劳、感染、呕吐、食欲减退、血红细胞计数降低、血小板计数减少以及白细胞组成减少。Istodax可能引起心电图（ECG）改变。在伴有某些心律异常风险的患者中应考虑做定期的血液检验以监测电解质，以及定期的ECG监测.

ISTODAX

Indication(s):

Cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Pharmacology:

Histone deacetylases catalyze the removal of acetyl groups from acetylated lysine residues in histones and non-histone proteins, affecting the expression of genes. Inhibitors of this enzyme, such as romidepsin, interfere with activities mediated by histones and transcription proteins. In vitro, romidepsin has been shown to cause the accumulation of acetylated histones and to induce cell cycle arrest and apoptosis in some cancer cell lines, but its exact mechanism of action in treating CTCL has not been elucidated.

Clinical Trials:

Two multicenter, single-arm clinical studies were used to evaluate the efficacy of romidepsin in treating CTCL. Patients were treated with the study drug at the recommended dose until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated using a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells. The primary endpoint for each study was overall objective disease response rate (ORR), defined as the proportion of patients with confirmed complete response or partial response.

Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. The ORR in this study was 34% (complete response 6% + partial response 28%). Median duration of response was 15 months.

Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or at least one systemic therapy. In this study, the ORR was 35% (complete response 6% + partial response 30%). Median duration of reponse was 11 months.

The median time to first response was 2 months in both studies. The median time to complete response was 6 months in Study 1 and 4 months in Study 2.

Legal Classification:

Rx

Adults:

≥18yrs: Give by IV infusion over 4hrs. 14mg/m² on days 1, 8, and 15 of a 28-day cycle; repeat cycle every 28 days; continue as tolerated and as beneficial. May interrupt, reduce dose to 10mg/m², or discontinue based on toxicities (see literature).

Children:

<18yrs: not recommended.

Precaution(s):

Correct electrolyte imbalances (esp. K⁺, Mg⁺⁺) before starting. Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Moderate to severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may cause fetal harm). Nursing mothers: not recommended.

Interaction(s):

May interfere with hormonal (estrogen) contraceptives. Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-glycoprotein and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, nefazodone). Caution with moderate CYP3A4 inhibitors. Antagonized by strong CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin; avoid. Concomittant St. John’s Wort: not recommended.

Adverse Reaction(s):

GI upset, fatigue, infections, anorexia, anemia, thrombocytopenia, ECG T-wave changes, neutropenia, lymphopenia.

How Supplied:

Kit—1 (single-use vial + diluent and supplies)

Last Updated:

3/4/2010