A Clinical Trial: Adjuvant Low-dose Ipilimumab + Nivolumab After Resection of Melanoma Macrometastases — ipniv  

Stage IV Skin Melanoma Clinical Trial

Official title: A Phase IB Clinical Trial on Adjuvant Low-dose Ipilimumab Plus Nivolumab Following the Resection of Melanoma Macrometastases

Status Completed

Clinical Trial Summary

Nivolumab (OpdivoTM, BMS), a human IgG-4 anti-PD-1 monoclonal antibody has demonstrated anti-tumor activity in patients with advanced melanoma.

The investigators postulate that patients with melanoma nivolumab have a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks.

Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma. Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma (EORTC 18071).

Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events (CheckMate 067).Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.

Clinical Trial Description

Currently, there is no standard of care or no available treatment for subjects with AJCC Stage IIIb/c and Stage IV NED melanoma who are at high risk for recurrence following complete resection of their metastasis. Ipilimumab (10mg/kg), interferon, pegylated interferon therapy or observations alone are the typical options for the Stage III patients who achieve a complete resection and are Food and Drug Administration (FDA) approved. In the EU, high-dose interferon is the only approved drug for the adjuvant treatment of melanoma patients. Given the unexceptional benefit and high toxicity profile in a patient population that is free of disease, it is controversial whether ipilimumab and interferon can be considered standard of care for Stage III melanoma. Nivolumab, a PD1 blocking monoclonal antibody, has shown superior anti-tumor activity across a wide range of dose-levels (0,1 to 10 mg/kg every 2 weeks) in patients with advanced melanoma. Nivolumab (at a dose of 3 mg/kg every 3 weeks) demonstrated a survival benefit in treatment naive patients with BRAF Wild Type (WT), metastatic melanoma in a Phase 3, randomized clinical trial and a PFS benefit over ipilimumab as a first-line therapy for advanced melanoma. Combination therapy with ipilimumab and nivolumab results in a higher response rate and PFS as compared to the results obtained with monotherapy. Combination therapy however significantly increases the incidence of grade > 3 adverse events, to the extent that this regimen would probably be associated with unacceptable toxicity in the adjuvant setting. The toxicity seems to be driven by Ipilimumab. The adverse events seen on Ipilimumab are dose dependent.

Unlike PD-1 blockade, CTLA-4 blockade diversifies the peripheral T-cell pool, representing a pharmacodynamic effect that can be measured by a DNA-sequencing technology referred to as ImmunoSeq.

This phase IB study will investigate the effect of low-dose ipilimumab and low-dose nivolumab on the peripheral T-cell repertoire of patients who are free of disease following the resection of melanoma macrometastases.

Treatment with low-dose ipilimumab in combination with low-dose nivolumab will be safe and modify the peripheral T-cell repertoire in subjects with completely resected Stage IIIb/c and Stage IV melanoma who are at high risk for recurrence.

Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma .Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma .

Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events.

Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes. ;

Related Conditions & MeSH terms

• Melanoma
• Stage IIIC Skin Melanoma
• Stage IV Skin Melanoma

• NCT number: NCT02941744
• Study type: Interventional
• Source: Universitair Ziekenhuis Brussel
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2016
• Completion date: January 2019