Currently, standard treatment options available for Stage III melanoma include locoregional management (i.e. surgery) or systemic treatment (adjuvant to surgery or primarily in the case of unresectable disease). Adjuvant treatment options have shown major improvements in overall survival (OS) and relapse free survival (RFS) in resected stage III or IV melanoma. In daily practice, T-VEC monotherapy is used for unresectable Stage IIIB-IVM1a (injectable) disease, whereas Nivolumab is used for stage IV melanoma (among other systemic therapies). The next major developments are in neo-adjuvant treatment options for resectable stage III disease, where 3 small studies reported high response rates with systemic immunotherapy. This study evaluates the combination treatment of T-VEC + Nivolumab in the neo-adjuvant setting. The concept is that T-VEC can turn an immune desolate "cold" tumor into an immunogenic "hot" tumor. The hypothesis is that this will upregulate the expression of PD-L1 and make it more susceptible for treatment with an anti-PD-1 agent. The investigators believe neo-adjuvant Nivolumab + T-VEC will thus change the tumor microenvironment in patients with stage IIIB/C/D/IVM1a (AJCC 8) melanoma with resectable cutaneous or subcutaneous satellite or in-transit metastases (ITM) and/or tumor positive lymph nodes. With this trial the investigators aim to determine safety and feasibility of combination neo-adjuvant Nivolumab + T-VEC in patients with stage III melanoma with resectable ITM and/or tumor positive lymph nodes. The treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intravenous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 108 PFU/mL is given every 2 weeks (± 3) days after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 106 PFU/mL to allow for seroconversion) , and Nivolumab can be given either every 2 weeks or every 4 weeks. Therefore we suggest the same dosing schedule for T-VEC and Nivolumab every 2 weeks for the purpose of this trial.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
The treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intraveneous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T-cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 10\^8 PFU/mL is given every 2 weeks after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 10\^6 PFU/mL to allow for seroconversion), and Nivolumab will be given every 2 weeks.
Antoni van Leeuwenhoek ziekenhuis
Amsterdam, North Holland, Netherlands
Pathologic response
Pathologic response according to central revision by pathology of NKI (complete response, near complete response (\<10% vital tumor remaining)
Time frame: 12 weeks
Rate of delay of surgery > 14 days
Time frame: 9 weeks
Rate of failure to perform surgery defined as no surgery at all (due to progressive disease or adverse events)
Time frame: 9 weeks
Relapse free survival (RFS)
Relapse free survival as defined from date of surgery until date of first relapse (regardless of site)
Time frame: Up to 2 years after treatment
Safety of neo-adjuvant combination of T-VEC and nivolumab according to CTCAE v5.0
Time frame: 12 weeks
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example CD8
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example IFN-γ
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example PD-L1
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for exploration of expansion of tumor-resident T cells in the tumor
Time frame: Up to 2 years after treatment
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