近日，美国FDA批准Beleodaq(belinostat)用于外周T细胞淋巴瘤(PTCL)患者治疗，PTCL是一种罕见并快速增长的非霍奇金淋巴瘤(NHL)。这次的批准是在FDA加速批准程序下完成。PTCL由不同组的疾病组成，这类疾病的淋巴结发生癌变。2014年，美国国家癌症研究所预测70800名美国人将被确诊为NHL，而有18990人会死亡。在北美PTCL占NHLs的比例大约在10%到15%。Beleodaq通过阻止有助于T细胞（一种免疫细胞）发生癌变的酶起作用。这款药物适用于治疗后（复发性）疾病又卷土重来或对以前治疗无效（难治性）的患者。
批准日期：2014年7月3日；公司: Spectrum药业公司
BELEODAQ（贝利司他[belinostat]）用于注射，用于静脉注射
美国最初批准：2014年
作用机制
Beleodaq是一种组蛋白去乙酰化酶（HDAC）抑制剂。HDAC催化从组蛋白的赖氨酸残基和一些非组蛋白蛋白中除去乙酰基。在体外，belinostat引起乙酰化组蛋白和其他蛋白质的积累，诱导一些转化细胞的细胞周期停滞和/或凋亡。
与正常细胞相比，Belinostat显示出对肿瘤细胞的优先细胞毒性。Belinostat以纳摩尔浓度（<250 nM）抑制组蛋白脱乙酰酶的酶活性。
适应症和用法
Beleodaq是一种组蛋白去乙酰化酶抑制剂，适用于治疗复发或难治性外周T细胞淋巴瘤（PTCL）的患者。基于肿瘤反应和反应持续时间，在加速批准下批准该指示。尚未确定存活率或疾病相关症状的改善。对该指征的持续批准可能取决于验证试验中临床获益的验证和描述。
剂量和给药
Beleodaq的推荐剂量为1000mg/m2，通过静脉输注在21天周期的第1-5天每天一次施用30分钟。可以重复循环直至疾病进展或不可接受的毒性。
为了控制不良反应，可能需要治疗中断或中断，有或没有剂量减少25％。
剂量形式和强度
用于注射：500mg，在单剂量小瓶中的冻干粉末用于重构。
禁忌症
没有。
警告和注意事项
血液学毒性：血小板减少症，白细胞减少症（中性粒细胞减少症和淋巴细胞减少症）和贫血症：监测血细胞计数并改变血液毒性的剂量。
感染：严重和致命的感染（例如，肺炎和败血症）。
肝毒性：Beleodaq可能引起肝毒性和肝功能试验异常。监测肝功能检查并省略或修改肝脏毒性剂量。
肿瘤溶解综合征：监测患有晚期疾病和/或高肿瘤负荷的患者并采取适当的预防措施。
胚胎 - 胎儿毒性：Beleodaq给孕妇服用可能会造成胎儿伤害。告知女性在接受Beleodaq时可能对胎儿造成伤害并避免怀孕。
不良反应
最常见的不良反应（> 25％）是恶心，疲劳，发热，贫血和呕吐。
要报告疑似不良反应，请致电1-888-292-9617联系SpectrumPharmaceuticals，Inc。或致电1-800-FDA-1088或www.fda.gov/medwatch与FDA联系
用于特定人群
护理母亲：在Beleodaq治疗期间，应建议女性不要母乳喂养。
包装提供/存储和处理
提供
注射用Beleodaq（belinostat）以单瓶小瓶供应; 每个30mL透明小瓶含有相当于500mg belinostat的无菌冻干粉末。
NDC 68152-108-09：Beleodaq 30 mL单剂量小瓶的个别纸盒，含有500 mg belinostat。
存储和处理
存放Beleodaq（belinostat），室温20°C至25°C（68°F至77°F）。偏差可在15°C至30°C（59°F至86°F）之间进行。 保留原包装直至使用。[见USP ControlledRoom温度]。
Beleodaq是一种细胞毒性药物。 遵循特殊处理和处理程序[见参考文献]。
完整说明资料附件：http://beleodaq.com/downloads/Beleodaq_PI.pdf
FDA Grants Spectrum Pharmaceuticals Accelerated Approval of Beleodaq™ (belinostat) for Injection
•Early Action before PDUFA date of August 9, 2014 follows Priority Review
•Beleodaq to be launched through Spectrum's existing sales force
•Beleodaq is expected to be available to patients in less than 3 weeks
important unmet medical need for these patients with PTCL for additional new treatment options that are specifically effective for this disease.
“This FDA approval enables us to help address this unmet medical need, and provide a new treatment option for patients with this difficult-to-treat and ultimately fatal disease,” said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. “First with Folotyn® (pralatrexate injection) and now with Beleodaq, we are very proud to be able to offer patients and clinicians two approved treatment options for R/R PTCL, and be a leader in the treatment of T-cell lymphomas. We will be able to effectively leverage our existing Hematology clinical and sales infrastructure to expedite the launch of Beleodaq. Now with a total of five approved Hematology/Oncology drugs and a strong and maturing development pipeline, Spectrum is well positioned for continued future growth.”
“Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care,” said Owen A. O'Connor, MD, PhD, Director of Lymphoid Malignancies, Professor of Medicine and Experimental Therapeutics at Columbia Medical Center, New York Presbyterian Medical Center, one of the lead investigators in the BELIEF study. “Relapse is common after initial treatment, and there are limited options for patients in 2nd line and beyond. Histone deacetylase inhibitors have emerged as one promising class of drugs for patients faced with this disease. One interesting observation in the study was the tolerability of Beleodaq in these heavily treated patients. Beleodaq was associated with myelosuppression with an overall rate of anemia of 32%, thrombocytopenia of 16.3% and neutropenia of 9.3% and Grade 3/4 adverse reactions were reported in 10.9%, 7.0% and 6.2% of patients, respectively. The associated severity of hematologic toxicities may prove to be useful in previously treated patients who have poor bone marrow reserve.”
“Interestingly, Beleodaq was shown to have an Overall Response Rate of 25.8% with a high response rate (45.5%) in patients with Angioimmunoblastic T-cell Lymphoma, one of the common PTCL subtypes. In addition, 17% of the patients enrolled in this trial had low Baseline platelet counts ( < 100,000/mm3) and tolerated therapy with some (15%) attaining partial and complete responses. I believe Beleodaq will be a valuable new option for physicians who treat patients with relapsed or refractory PTCL. This safety profile makes it a potential candidate for the development of new combination treatment paradigms for patients with PTCL,” added Dr. O'Connor.
A review of data from a planned confirmatory Phase III trial of Beleodaq in combination with CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone), to characterize the efficacy and safety of the Beleodaq combination versus CHOP alone, is required by FDA to convert this Accelerated Approval to a Full Approval.
BELIEF STUD
The BELIEF study was an open-label, single-arm, non-randomized, international trial conducted at 62 centers that enrolled 129 patients with relapsed or refractory PTCL; 120 patients had histologically confirmed PTCL by central review and were eva luable for efficacy. Patients received treatment with Beleodaq (1,000 mg/m2), administered over 30 minutes via IV infusion, once daily on Days 1-5 of a 21-day cycle. Treatment cycles were repeated every three weeks until disease progression or unacceptable toxicity.
The primary efficacy endpoint of the BELIEF study was Overall Response Rate (complete and partial responses) as assessed by an Independent Review Committee (IRC) using the International Workshop Criteria (IWC) (Cheson, 2007). The key secondary efficacy endpoint was Duration of Response. In all eva luable patients (N = 120) treated with Beleodaq, the Overall Response Rate (CR + PR) per central review using IWC was 25.8% (n = 31; 95% CI, 18.3 – 34.6); with rates of 23.4% for PTCL, NOS and 45.5% for AITL, the two largest subtypes enrolled. The median Duration of Response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 - 29.4).
Data from the BELIEF study demonstrated that the most common adverse events (AEs) reported with Beleodaq (>25%) were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%). Myelosuppression was observed with an overall rate of anemia of 32%, thrombocytopenia of 16.3% and neutropenia of 9.3%; Grade 3/4 adverse reactions were reported in 10.9%, 7.0% and 6.2% of patients, respectively. Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. The most common serious adverse reactions (>2%) were pneumonia (7%), pyrexia (5%), infection (3%), anemia (2%), increased creatinine (2%), thrombocytopenia (2%), and multi-organ failure (2%).
Spectrum Pharmaceuticals (SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, announced today that the U.S. Food and Drug Administration (FDA) has granted Accelerated Approval of Beleodaq™ for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is approved under accelerated approval based on Tumor Response Rate and Duration of Response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
Beleodaq was approved by the FDA on July 3rd, nearly 5 weeks before the PDUFA date (August 9th). This indication was approved based on data from the multi-center, single-arm BELIEF trial in 120 eva luable patients, refractory to or who had failed at least one prior systemic therapy. In this trial, Beleodaq was associated with hematologic toxicity, infections, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity.
PTCL comprises a group of rare and aggressive non-Hodgkin’s Lymphomas (NHL) that develop from mature T-cells and accounts for approximately 10 to 15% of all NHL cases in the United States. These patients generally have a poor prognosis with a low response rate (25-27%) to available treatment options, and commonly experience repeated treatment failures until drug resistance or death. Therefore, there has been an About BELEODAQ™
Beleodaq is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (< 250 nM).
Important Beleodaq Safety Information
Warnings and Precautions
•Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary.
•Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections.
•Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities. Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity.
•Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL. Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions.
•Nausea, vomiting and diarrhea occur with Beleodaq and may require the use of antiemetic and antidiarrheal medications.
•Beleodaq can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus.
Adverse Reactions
•The most common adverse reactions observed in the trial in patients with relapsed or refractory PTCL treated with Beleodaq were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%).
Drug Interactions
•Beleodaq is primarily metabolized by UGT1A1. Avoid concomitant administration of Beleodaq with strong inhibitors of UGT1A1.
Use in Specific Populations
•It is not known whether Beleodaq is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Beleodaq, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.
Please see Beleodaq Full Prescribing Information at www.beleodaq.com.