Phase Ib/II study exploring safety and efficacy of the combination of ipilimumab with radiofrequency ablation (RFA) in patients with unresectable uveal melanoma liver metastasis (SECIRA-UM)

Uveal melanoma is an uncommon malignancy (0.6-0.7 cases/100.000/year) that, in
the case of metastatic stage, has a poor prognosis for response to treatment
and survival. It is remarkable for its purely hematogenous pattern of
dissemination, most commonly to the liver (60%) and lungs (25%). Only 28 phase
I-II studies were performed in uveal melanoma patients between 1980 and 2008,
none of them showing convincing
improvements of overall survival rates. Current approaches using
chemoembolization with cisplatin-based regimens or intrahepatic artery
administration of fotemustin resulted in response rates of up to 40% without
increasing the overall survival rates beyond 12 months. Ipilimumab has been
shown to improve OS in cutaneous melanoma in two phase III studies and seems to
have activity in uveal melanoma, based on own experience from another group.
Based on preclinical data and the observed activity of ipilimumab monotherapy
in uveal melanoma this study will test the safety and efficacy of a combination
of RFA and ipilimumab in uveal melanoma patients that have unresectable liver
metastases.

To evaluate the safety and efficacy of the combination of RFA and Ipilimumab in
patients with unresectable, pathologically confirmed hepatic metastases of
uveal melanoma.

This is an open label, non-randomized, single centre, mono-arm phase II trial,
evaluating the efficacy (as measured by RECIST 1.1) and safety of the
combination of RFA and Ipilimumab in patients with at least two unresectable
hepatic metastases of uveal melanoma in first line systemic treatment. A total
of maximally 44 patients will be treated in this study. At first the patients
will be treated in cohorts of 3 patients. The first cohort receives 0,3 mg/kg
ipilimumab, the second 3,0 mg/kg and the third 10 mg/kg. The optimal dose will
be given to up to 38 patients in total.

The patients will undergo radiofrequency ablation on a liver metastasis, and a
biopsy will be taken from a liver metastasis. After that the patients will
receive 4 courses of ipilimumab. Also biopsies will be taken after the 4
courses ipilimumab.

Results from the two phase 3 studies indicate that Ipilimumab in advanced
melanoma is active and offers 2-year survival rates
ranging from 23.5% (single treatment) to 28.5% (in combination with DTIC).
Of the 28 phase I-II studies that were performed in uveal melanoma patients
between 1980 and 2008 none of them showed
improvements of OS rates not attributable to patient selection. Recent
approaches using chemoembolization with cisplatin-based
regimens or intrahepatic artery administration of fotemustin resulted in local
response rates of up to 40% without any systemic
responses, nor improving the OS.
Therefore it must be concluded, that there is no standard therapy for stage IV
uveal melanoma patients available.
Substantial reductions in total tumor burden, including widely disseminated
disease in the skin, lung, and/or other visceral disease
sites, were reported upon Ipilimumab treatment in non-ocular melanoma. More
than half the responses were reported in subjects
staged with M1b or M1c advanced melanoma disease, which is most resistant to
approved therapies.
Only minor experience from the extended access program is available concerning
the activity of Ipilimumab in uveal melanoma, and
only preclinical data are available indicating synergism between Ipilimumab and
RFA treatment (see Section 1.2 of the protocol).
Characteristic organ-specific inflammatory irAEs were reported with Ipilimumab
therapy, typically during induction therapy. IrAEs were
mostly reversible within days to weeks following cessation of therapy or
treatment with symptomatic therapy, corticosteroids or other
anti-inflammatory agents, depending upon severity. Accumulated clinical
experience resulted in detailed toxicity management
guidelines (also termed algorithms, Appendix B), by use of which irAEs can be
effectively managed, especially when irAEs are
recognized early and subjects are treated in a timely fashion. This can
minimize the occurrence of irAE complications, such as GI
perforation/colectomy or hepatic failure.
Percutaneous RFA of metastases can be considered as a safe procedure with a
mortality rate ranging from 0%-0.3% and major
complications rate ranging from 0.9-4.6%.
RFA of a liver metastasis might induce an inflammatory signal within the liver
that lead to a higher chance of ipilimumab-induced
autoimmune-hepatitis than observed in Ipilimumab single treatment. Indeed,
grade 3 or 4 hepatitis was not observed in phase II and III
trials using Ipilimumab at 3mg/kg as monotherapy, while in combination with
gp100 vaccination or DTIC chemotherapy hepatitis well
in the range of 0.3-1.2%. Therefore, this irAE has been defined as a major DLT
to be considered at the early patients analysis for the
study stopping rule.
Considering the unmet medical need in uveal melanoma, and the observed systemic
responses in the expanded access program
treating uveal melanoma patients, the overall risk-benefit ratio for uveal
melanoma patients entering this protocol is, therefore, at
least comparable to or even better than alternative best supportive care
options.