Department of Medical Oncology, Leiden University Medical Center, PO Box 9600, 2300, RC, Leiden, The Netherlands.
Department of Radiology, Leiden University Medical Center, PO Box 9600, 2300, RC, Leiden, The Netherlands.
Trials. 2022 Feb 13;23(1):137. doi: 10.1186/s13063-022-06036-y.
While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease.
Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.
This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver.
This trial was registered in the US National Library of Medicine with identifier NCT04283890 . Registered as per February 2020 - Retrospectively registered. EudraCT registration number: 2018-004248-49. Local MREC registration number: NL60508.058.19.
免疫检查点抑制（ICI）已经彻底改变了转移性皮肤黑色素瘤的治疗方法，但对于转移性葡萄膜黑色素瘤（UM）患者，尚无标准治疗方法。几种局部区域治疗方法对治疗肝转移有效，例如甲氨蝶呤（M-PHP）经皮肝灌注。现有文献表明，在局部区域治疗肝 UM 转移后使用 ICI 治疗可导致临床反应。我们假设将 M-PHP 与 ICI 联合使用将导致抗原呈递增强和免疫调节作用增强，从而改善对肝内和肝外疾病的控制。
这是一项开放标签、单中心、Ib 期/随机 2 期试验，评估了在一线治疗中不可切除的 UM 肝转移患者中，M-PHP 联合 ipilimumab（抗 CTLA-4 抗体）和 nivolumab（抗 PD-1 抗体）的安全性和有效性，同时伴有或不伴有有限的肝外疾病。主要目标是确定联合治疗方案的安全性、毒性和疗效，定义为最大耐受剂量（MTD）和 1 年时无进展生存期（PFS）。次要目标包括总生存期（OS）和总缓解率（ORR）。在 I 期和 2 期联合治疗中，最多将有 88 例患者接受治疗。将使用描述性统计（t 检验、卡方检验）描述基线特征。为了研究危险因素与毒性之间的关联，将应用逻辑回归模型。将使用 Kaplan-Meier 曲线总结 PFS 和 OS。
这是第一项通过确定最大耐受剂量并评估联合治疗疗效来评估这种治疗组合的试验。M-PHP 已被证明是治疗 UM 肝转移患者的安全有效的方法，并且已成为我们中心的标准治疗选择。目前描述的试验正在研究 ICI 与 M-PHP 的联合使用，这可能会导致肝脏内外的治疗反应更好。
该试验在美国国立医学图书馆注册，标识符为 NCT04283890。于 2020 年 2 月注册-回顾性注册。EudraCT 注册号：2018-004248-49。当地 MREC 注册号：NL60508.058.19。
