在优先审评药物计划下Xofigo比计划提前三个月被批准。新分子实体
2013年5月15日美国食品药品监督管理局(FDA)批准Xofigo(二氯化镭223[镭 Ra 223 dichloride])治疗有症状性晚期(转移)趋势耐药前列腺癌已播散至骨但不是其他气管的男性。药物意向为较低睾丸酮接受药物或外科治疗后其癌症已播散的男性。
前列腺癌在膀胱下和直肠前的发现的男性生殖系统腺体中形成。男性性激素睾丸酮刺激前列腺肿瘤生长。按照美国国家癌症研究所，2013年估计238,590男性将被诊断为前列腺癌而29,720 死于该病。
Xofigo比处方药物产品用户免费目标日期2013年8月14日，将举计划完成药物申请审评日期提前三个月被批准。FDA在监管局优先审评程序下审评Xofigo，当不存在满意的另外治疗或提供对上市产品显著改善时，这个程序提供加快审评表现提供安全和有效治疗。
FDA的药物评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“Xofigo与骨中矿物质结合直接释放辐射至骨肿瘤，限制对周围正常组织的损伤，”“Xofigo是在去年被FDA批准的显示有延长转移前列腺癌男性生命的第二个前列腺癌药物”。
2012年8月，FDA批准Xtandi治疗有转移趋势耐药前列腺癌已播散或复发，甚至有药物或外科治疗以尽量减少睾丸酮的男性。Xtandi被批准为既往曾被化疗药物多西紫杉醇在[docetaxel]治疗的患者。
在一项809例有症状性趋势耐药前列腺癌播散至骨但不是其他气管男性的单次临床试验评价Xofigo的安全性和有效性。患者被随机化赋予接受Xofigo或一种安慰剂加最佳标准医护。
研究被设计测量总体生存。来自一项预先计划的中期分析结果显示接受 Xofigo男性生存中位数14个月与之比较对接受安慰剂男性中位数11.2个月。以后进行试验的一项探索性更新分析证实Xofigo延长总体生存的能力。
接受 Xofigo男性临床试验期间报道最常见副作用是恶心，腹泻，呕吐和腿，踝或足肿胀。血液测试期间检测到的最常见异常包括低水平红细胞(贫血)，淋巴细胞(淋巴细胞减少)，白细胞(白细胞减少)，血小板(血小板减少)和感染斗争白细胞(中性粒细胞减少).
Xofigo由Wayne，总部在新泽西的Bayer药业上市。Xtandi被美国Astellas Pharma，Inc. orthbrook，Ill.，和加州旧金山Medivation公司共同上市。
Indication
Xofigo® (radium Ra 223 dichloride) injection is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.
Important Safety Information
•Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman
•Bone Marrow Suppression: In the randomized trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo.
Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure
•Hematological eva luation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care
•Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued
•Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations
•Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo‑treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%)
氯化镭-223（镭-223）能够发射α射线，利用这一特点使其选择性作用于前列腺癌的骨转移灶，可有效抑制疾病的进展。来自英国royal marsden医院泌尿科的parker博士等人对去势抵抗性前列腺癌和骨转移的患者，在予以最佳标准治疗之外，还评估了镭-223治疗的有效性和安全性。他们发现镭-223可改善总生存率，相关文献发表于国际权威杂志nejm2013年7月份在线版。
在该项3期、随机、 双盲、安慰剂对照研究中，研究人员对已经接受、不宜接受或拒绝接受多西他赛治疗的921例患者按2:1的比例进行随机分组，分别接受6次镭-223注射 （剂量为50kbq/公斤体重，静脉给药）或与之匹配的安慰剂治疗；每4周注射1次。此外，所有患者均接受最佳标准治疗。主要终点是总生存率，次要终点包括首次发生有症状的骨骼事件时间和不同生化指标终点。当出现314例死亡时，研究人员按预先试验设计进行了中期分析，评估了镭-223与安慰剂相比对生存率 的影响。
809例患者的中期分析提示，与安慰剂相比，镭-223可显著改善总生存率。包括921例患者的重新分析证实了镭-223的生存裨益。对所有主要次要有效性终点的评估显示了镭-223与安慰剂相比的裨益。镭-223与低骨髓抑制率和较少的不良事件相关。
这项研究因预先设定的中期分析显示有效而予以终止，最终得出结论：镭-223可改善总生存率。
研究背景：
超过90%的转移性去势抵抗性前列腺癌患者存在骨转移，这是患者死亡、致残、生活质量下降以及治疗成本上升的主要原因。与其他癌症导致的死亡不同，前列腺癌致死多由骨转移及并发症所致。目前的骨靶向治疗并未显示出可改善生存的迹象，而现有放疗的作用也仅仅局限于对疼痛的缓解和骨骼事件的延迟。
镭-223二氯化合物（镭-223）可以靶向骨转移患者的骨转换增强的区域，并发射短距离 (<100 μm)高能α粒子。作为一种骨亲和性钙仿生剂，镭-223高度靶向新生骨基质，特别是成骨细胞微环境或骨膜转移灶。这种高能α粒子放射可诱导双链dna损伤，进而导致细胞毒性效应。另外α粒子的短距效应意味着它对邻近健康组织特别是骨髓的毒性作用可达到最小化。
据报道，镭-223在安全性方面表现优异，1期和2期研究显示，这种疗法的骨髓毒性很低。镭-223还可减少疼痛并改善疾病相关的生物标志物（如骨碱性磷酸酶和前列腺癌特异性抗原），同时提示去势抵抗性前列腺癌及骨转移患者有生存获益。 |
