Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced uveal melanoma (CHOPIN): study protocol for a phase Ib/randomized phase II trial

T M L Tong, M K van der Kooij, F M Speetjens, A R van Erkel, R W van der Meer, J Lutjeboer, E L van Persijn van Meerten, C H Martini, R W M Zoethout, F G J Tijl, C U Blank, M C Burgmans, E Kapiteijn, T M L Tong, M K van der Kooij, F M Speetjens, A R van Erkel, R W van der Meer, J Lutjeboer, E L van Persijn van Meerten, C H Martini, R W M Zoethout, F G J Tijl, C U Blank, M C Burgmans, E Kapiteijn

Abstract

Background: 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.

Methods: 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.

Discussion: 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.

Trial registration: 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.

Keywords: Advanced uveal melanoma; Immunotherapy; Liver metastases; Percutaneous hepatic perfusion.

Conflict of interest statement

E. Kapiteijn has served as an advisory board member for Bristol-Myers Squibb. This contribution has been paid to the institution. The other authors declare no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Inclusion and exclusion criteria. WHO, World Health Organization; UM, uveal melanoma; WBC, white blood cell; AST, aspartate aminotransferase; ULN, upper limit of normal; ALT, alanine aminotransferase; INR, international normalized ratio; PTT, partial thromboplastin time; LDH, lactate dehydrogenase; M-PHP, percutaneous hepatic perfusion with melphalan
Fig. 2
Fig. 2
Treatment scheme. C1, Cohort 1; C2, Cohort 2; CT th/abd, CT-scan of the chest and abdomen; MRI, magnetic resonance imaging; Chemosaturation, percutaneous hepatic perfusion; , PBMC; , CT Th/abd, MRI liver; , tumor biopsy
Fig. 3
Fig. 3
Flowchart establishment of MTD. DLT, dose limiting toxicity; MTD, maximum tolerated dose; DSMB, Data Safety Monitoring Board; ICI, immune checkpoint inhibitor (ipilimumab + nivolumab); M-PHP, percutaneous hepatic perfusion with melphalan

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