Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
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DOI：
10.1016/s1470-2045(12)70090-6
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发表时间：
2012-05-01
期刊：
影响因子：
51.1
通讯作者：
Hodi, F. Stephen
中科院分区：
文献类型：
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作者：
Margolin, Kim;Ernstoff, Marc S.;Hodi, F. Stephen
脑转移瘤通常发生在黑色素瘤患者中，并且是该疾病患者死亡的常见原因。Ipilimumab改善晚期黑色素瘤患者的生存率我们的目的是调查这种药物的安全性和活性，特别是在脑transferase.Methods患者之间的2008年7月31日，2009年6月3日，我们招募了黑色素瘤和脑转移瘤患者从10个美国中心谁是年龄超过16岁的两个平行队列。队列A中的患者在神经系统上无症状，并且在进入研究时未接受皮质类固醇治疗;队列B中的患者有症状，并且接受稳定剂量的皮质类固醇治疗。患者接受4次10 mg/kg伊匹单抗静脉给药，每3周一次。在第24周时临床稳定的个体有资格每12周接受10 mg/kg静脉内伊匹单抗。主要终点是疾病控制的患者比例，定义为12周后完全缓解、部分缓解或疾病稳定，采用改良的WHO标准进行评估。安全性和疗效分析包括所有接受治疗的患者。该试验在ClinicalTrials.gov注册，编号NCT 00623766。结果我们招募了72名患者：51名进入队列A，21名进入队列B。12周后，队列A中的9名患者表现出疾病控制（18%，95% CI 8-31），队列B中的1名患者也表现出疾病控制（5%，0.1-24）。当仅评估大脑时，队列A中的12名患者（24%，13-38）和队列B中的2名患者（10%，1-30）实现了疾病控制。我们注意到队列A中14例患者（27%，16-42）和队列B中1例患者（5%，0.1-24）的脑外疾病控制。队列A中最常见的3级不良事件为腹泻（6例患者[12%]）和疲乏（6例[12%]）;队列B中为脱水（2例患者[10%]）、高血糖（2例[10%]）和血清天冬氨酸转氨酶浓度升高（2例[10%]）。每个队列中各有1例患者出现4级意识模糊。队列A中最常见的3级免疫相关不良事件为腹泻（6例患者[12%]）和皮疹（1例[2%]），队列B中最常见的3级免疫相关不良事件为皮疹（1例[5%]）和血清天冬氨酸转氨酶浓度升高（2例[10%]）。队列A中的一名患者死于免疫相关性结肠炎的药物相关并发症。解释Ipilimumab在一些晚期黑色素瘤和脑转移患者中具有活性，特别是当转移灶较小且无症状时。该药物在该人群中没有意外的毒性作用。
Background Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases.Methods Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766.Findings We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0.1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0.1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis.Interpretation Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population.