Abstract
BackgroundWhile 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.MethodsOpen-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.DiscussionThis 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.Trial RegistrationThis 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.
Highlights
Background and rationale {6a} Uveal melanoma (UM) is the most common intraocular malignant tumor in adults [1]
In case of bone marrow toxicity ≥ grade 3 (according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v 4.03)) after the first Percutaneous Hepatic Perfusion with Melphalan (M-PHP)-procedure, a dose reduction of 25% will be applied at the second M-PHP
In the randomized phase II part of the study, we aim to demonstrate the superiority of combined M-PHP plus ipilimumab and nivolumab over M-PHP only based on the assumption that progression-free survival (PFS) at 1 year will increase from 20% in the M-PHP arm to 50% in the combination arm
Summary
Background and rationale {6a} Uveal melanoma (UM) is the most common intraocular malignant tumor in adults [1]. It is a rare type of malignancy, with an incidence of 4–7 cases per million in Europe [2]. Prognosis of metastatic UM remains dismal and has improved little over the last 30 to 40 years [1], since no standard treatment is available. 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
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