——美国FDA批准Unituxin为第一个治疗高风险神经母细胞瘤 近日，美国FDA批准Unituxin(Dinutuximab)作为一线治疗药物的一部分用于高风险神经母细胞瘤儿科患者，这种一种通常发生在幼儿身上的癌症。 神经母细胞瘤是一种罕见的癌症，它形成于不成熟的神经细胞。这种疾病通常起始于肾上腺，但还可能在腹部、胸部或脊柱附近的神经组织发展。神经母细胞瘤通常发生在五岁以下的儿童身上。 据美国国家癌症研究所提供的信息，神经母细胞瘤在儿童中的发病率大约为十万分之一，男孩中的发病率略高。美国每年预计会有650个神经母细胞瘤新病例被确诊。尽管进行积极治疗，但只有40%到50%的高风险神经母细胞瘤患者有长期生存的机会。 Unituxin是一种抗体，它可以绑定到神经母细胞瘤细胞的表面。Unituxin被批准用作综合治疗方案的一部分，包括手术、化疗及放射治疗，适用于对之前一线多种药物、综合治疗至少达到部分响应的患者。 "Unituxin标志着首款获批专门用于高风险神经母细胞瘤患者治疗的药物，"FDA药品评价与研究中心代谢及肿瘤产品办公室主任、医学博士Richard称。"Unituxin通过提供一种治疗选择满足了一个关键的需求，它可以延长高风险神经母细胞瘤儿童患者的生存期。" FDA授予了Unituxin优先审评及孤儿药资格。与标准审评相比，优先审评将这款药物申请的审评时间缩短了4个月，优先审评授予那些如果获得批准，将能对严重疾病治疗的安全性及有效性提供明显改善的药物。 孤儿药资格授予那些旨在治疗罕见疾病的药物。对于这次批准，FDA还向United Therapeutics发布了一项罕见儿科疾病审评券，它可授予以后不符合优先审评的一款药物申请优先审评。这是FDA自发起罕见儿科疾病审评券项目以来发布的第二个罕见儿科疾病优先审评，这一项目旨在鼓励用于某些罕见儿科疾病预防及治疗的新型治疗药物的开发。 Unituxin的安全性及有效性在一项由226名患有高风险神经母细胞瘤儿科受试者的试验中得到评价，这些患者的肿瘤在经多药化疗及手术后接受其它大剂量化疗后缩小或消失，他们后来接受骨髓移植支持及放射治疗。 受试者被随机配给一种口服维甲酸药物异维甲酸(RA)或Unituxin与白介素-2、粒细胞巨噬细胞集落刺激因子及RA的合并用药，粒细胞巨噬细胞集落刺激因子被认为可通过刺激免疫系统来增强Unituxin的活性。 治疗后3年，63%的Unituxin合并治疗受试者仍存活，并且肿瘤不再增长或复发，相比之下，仅以RA治疗的受试者只有46%的人达到这一结果。在一项更新的预后分析中，73%的Unituxin合并治疗受试者仍存活，相比之下，仅以RA治疗的受试者只有58%的人达到这一结果。 Unituxin携带一项黑框警告，提醒患者及卫生保健专业人员Unituxin可刺激神经细胞，引起严重疼痛，需要静脉注射麻醉剂进行治疗，还能引起神经损伤及危及生命的输注重反应，包括输液期间或完成后不久出现上呼吸道肿胀、呼吸困难及低血压。Unituxin还可能引起其它严重副作用，包括感染、眼部疾病、电解质异常及骨髓抑制。 Unituxin最常见副作用有剧烈疼痛、发热、低血小板计数、输液反应、低血压、血液盐水平低(低钠血症)、肝酶升高、贫血、呕吐、腹泻、低血钾、毛细管泄漏综合症(特点是大量血浆及其它血液成分从血管泄漏到邻近体腔和肌肉)、抗感染白细胞(中性粒细胞减少和淋巴细胞)数量降低、荨麻疹及低血钙。 批准日期：2015年3月10日；公司：United Therapeutics Corporation 作用机制 Dinutuximab与糖脂GD2结合。神经母细胞瘤细胞上和神经外胚层来源正常细胞上，包括中枢神经系统和周边神经，表达这个糖脂。Dinutuximab结合至细胞表面GD2和诱导GD2表达细胞至抗体-依赖细胞-介导细胞毒性(ADCC)和补体-依赖细胞毒性(CDC)的细胞溶解。 适应证和用途 Unituxin(dinutuximab)是适用与粒细胞 - 巨噬细胞集落刺激因子(GM-CSF)，白介素-2(IL-2)和13-顺 - 视黄酸(RA)联用，为有高风险神经母细胞瘤对以前一线多药，多模式治疗前至少实现一个部分缓解反应儿童患者的治疗。 剂量和给药方法 每个疗程Unituxin开始前证实患者有适当血液学，呼吸，肝，和肾功能。 每次Unituxin输注开始前需要给予预先药物和水化。 推荐剂量 Unituxin的推荐剂量是17.5mg/m2/day历时10至20小时静脉输注给予共4连续天共最大5个疗程。 输注速率开始为0.875 mg/m2/hour共30分钟。输注速率可被逐渐地增加当对最大速率1.75 mg/m2/hour耐受。遵循对不良反应剂量调整指导。 完整说明书附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d66bdf0d-9d65-45de-ae5b-a58617c27492 Unituxin (dinutuximab) is a chimeric monoclonal antibody. Unituxin is specifically indicated for use in combination with granulocyte-macrophage colonystimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Unituxin is supplied as a solution for intravenous infusion. The recommended dose of Unituxin is 17.5mg/m2/day administered as an intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Unituxin should be initiated at an infusion rate of 0.875 mg/m2 /hour for 30minutes. The infusion rate can be gradually increased as tolerated to a maximum rate of 1.75mg/m2/hour. Follow dose modification instructions (see drug label) for adverse reactions. UNITUXIN Rx Pharmacological Class: GD2-binding monoclonal antibody. Active Ingredient(s): Dinutuximab 3.5mg/mL; solution for IV infusion after dilution; preservative-free. Company United Therapeutics Corp Indication(s): In combination with granulocyte-macrophage colony-stimulating factor, interleukin-2 (IL-2) and 13-cis-retinoic acid (RA), for the treatment of children with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Pharmacology: Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Clinical Trials: The safety and efficacy of Unituxin was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma. Patients were randomized between Day 50 and Day 77 post-autologous stem cell transplantation. Patients randomized to the Unituxin/RA arm (n=113) received up to five cycles of dinutuximab in combination with GM-CSF or IL-2 plus RA, followed by one cycle of RA alone. Patients randomized to the RA arm (n=113) received six cycles of RA. Dinutuximab was administered at a dose of 17.5mg/m2/day on four consecutive days. Patients in both treatment arms received six cycles of RA at a dose of 160mg/m2/day orally (for patients weighing >12kg) or 5.33mg/kg/day (for patients weighing ≤12kg) in two divided doses for 14 consecutive days. The major efficacy outcome measure was investigator-assessed event-free survival (EFS), defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. There were 33 (29%) events in the Unituxin/RA arm vs. 50 (44%) in the RA arm (HR 0.57; [95% CI: 0.37, 0.89]; P= 0.01). Overall survival (OS) was also evaluated. After observing improvement in EFS based on the seventh interim analysis, termination of accrual was recommended. For more clinical trial data, see full labeling. Legal Classification: Rx Adults: Not applicable. Children: Confirm adequate hematologic, respiratory, hepatic, and renal function prior to each course. Hydrate and premedicate with antihistamines, analgesics (eg, IV opioids), and antipyretics prior to each dose: see full labeling. Give via IV infusion over 10–20 hours for 4 consecutive days; max 5 cycles. Initial rate: 0.875mg/m2/hr for 30mins; may gradually increase as tolerated up to max 1.75mg/m2/hr. Cycles 1, 3, and 5 (24-day cycle): 17.5mg/m2/day on Days 4–7. Cycles 2 and 4 (32-day cycle): 17.5mg/m2/day on Days 8–11. Dose modifications: see full labeling. Warnings/Precautions: Risk of serious infusion reactions; monitor during and at least 4 hours after completion of each infusion; interrupt or discontinue if severe or prolonged infusion reactions occur. Have resuscitative medications and equipment available. Risk of neuropathy. Permanently discontinue if life-threatening infusion reactions, Grade 3 pain unresponsive to max supportive measures, Grade 4 sensory neuropathy or Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, Grade 2 peripheral motor neuropathy, recurrent signs of eye disorders or vision loss, signs of atypical hemolytic uremic syndrome occurs. Interrupt or discontinue if severe capillary leak syndrome, symptomatic hypotension, systolic BP less than lower limit of normal for age or decreased by >15% compared to baseline develops. Monitor for systemic infection; temporarily discontinue until resolves. Monitor BP, peripheral blood counts during therapy, and serum electrolytes daily. Renal or hepatic impairment. Pregnancy; avoid. Use effective contraception during therapy and for at least 2 months after last dose. Nursing mothers: not recommended. Adverse Reaction(s) Pain, pyrexia, infusion reactions, hypotension, hyponatremia, hypokalemia, hypocalcemia, hypoalbuminemia, increased ALT/AST, vomiting, diarrhea, capillary leak syndrome, urticaria, infections, bone marrow suppression (eg, thrombocytopenia, anemia, neutropenia, lymphopenia). How Supplied: Single-use vial (5mL)—1 LAST UPDATED: 7/7/2015