Phase 1b/2 Study Combining Hepatic Percutaneous Perfusion with Ipilimumab plus Nivolumab in advanced Uveal Melanoma

Uveal melanoma (UM) is an uncommon malignancy (0.6-0.7 cases/100.000/year)
that, in the case of metastatic stage, has a poor prognosis regarding response
to treatment and survival. It is remarkable for its purely hematogenous pattern
of dissemination, most commonly to the liver (60%) and lungs (25%). Even after
successful treatment of the primary tumor (either by enucleation or local
radiotherapy) dissemination occurs within 5 years in over 30% of patients (and
within 15 years in approximately 50%) resulting in median survivals ranging
from 2-12 months in unselected groups and 5-24 months in selected case series.
A retrospective analysis of 112 patients indicated that surgical resection in
patients with single metastasis has been the only treatment modality
correlating with improved survival (predominantly in patients with extrahepatic
metastases).
Checkpoint inhibitors have been shown to improve overall survival in
metastasized cutaneous melanoma in phase III studies, but seem to have limited
activity as monotherapies in metastasized uveal melanoma. The combination of
ipilimumab and nivolumab has achieved a partial response (PR) in 2/6 patients
in a retrospective analysis. Interestingly, both patients had a liver-directed
therapy before (SIRT and chemoembolization) upfront the immunotherapy.
Combination of radio-frequency ablation (RFA) and anti-CTLA-4 enhanced
antigen-loading of dendritic cells, and induced long-lasting anti-tumor immune
response in a murine melanoma model without induction of any severe side
effects. A phase Ib/II trial by Blank et al. showed unconfirmed responses in
some patients when RFA was combined with ipilimumab in uveal melanoma but
long-term disease stabilization was not achieved. Most of the responses were
seen in extrahepatic metastases.

This study has been transitioned to CTIS with ID 2024-516125-31-02 check the CTIS register for the current data.

Primary objective is to determine safety and tolerability, dose limiting
toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase dose
(RPTD) of the combination of ipilimumab/nivolumab and PHP in patients with
unresectable, histologically confirmed hepatic metastases of uveal melanoma in
the phase Ib part of the study. Furthermore, efficacy as defined by PFS at one
year, is investigated in the randomized phase II part.

Secondary objective(s) are to determine overall survival (OS), overall clinical
response (CR, PR, and SD as defined by RECIST 1.1 and iRECIST), and duration of
response (for patients achieving an objective response).

The phase 1b part of the study will test the safety of the combination of PHP
and ipilimumab/nivolumab in a 3+3 design, 3 patients per cohort. The study will
consist of 2 dose cohorts of each 3 patients, with an interval of 12 weeks
before opening the next dose escalation cohort after the last patient having
received the PHP+ipilimumab/nivolumab treatment.

After determining the maximum tolerable dose in phase Ib, the randomized phase
II part of the study will be continued. Randomization takes place on a 1: 1
basis between PHP versus PHP with ipilimumab and nivolumab. Description of
progression-free survival according to RECIST 1.1 will take place after 1 year,
in order to compare the PHP group with the PHP plus ipilimumab and nivolumab
group.

Uveal melanoma patients will undergo 2 percutaneous hepatic perfusion
procedures with or without 4 courses of the combination of ipilimumab and
nivolumab according to the schedule described in the clinical protocol.
Additionally, patients will undergo extra blood drawings and histological
punctures of metastases in the context of translational research.

For metastasized uveal melanoma patients, there are no standard treatment
options, apart from percutaneous hepatic perfusion in case of liver-only
disease. By combining PHP and checkpoint inhibitors, we hypothesize to induce
responses in both the hepatic and extra-hepatic metastases. Side-effects which
can be expected are the known grade 3 or 4 immune related adverse events of the
combination ipilimumab and nivolumab. These might increase in frequency because
of an extra boost to the immune system by adding PHP to ipilimumab/nivolumab.
We do not expect extra toxicity of the PHP-procedure itself by adding
ipilimumab/nivolumab to it, because ipilimumab/nivolumab will not lead to
anatomical or vascular changes. In the phase 1b part, safety and feasibility of
combining percutaneous hepatic perfusion with ipilimumab and nivolumab will be
investigated. In the open-label randomized phase 2 part, efficacy as measured
by progression-free survival at one year comparing PHP only versus PHP plus
ipilimumab/nivolumab will be evaluated.
Additional burden for the patients participating in this trial are extra blood
drawings and tumor biopsies.