What question did this study set out to answer?

The central aim is to assess if combining MDNA11 with nivolumab and ipilimumab improves major pathologic response in melanoma patients.

May 30, 2026

A multicenter, randomized phase Ib trial to evaluate neoadjuvant immunotherapy combination of nivolumab alone or plus ipilimumab with the IL-2 superkine MDNA11 alone or with tocilizumab in patients with high-risk, surgically resectable melanoma: The NEO-CYT trial.

Key Points

The central aim is to assess if combining MDNA11 with nivolumab and ipilimumab improves major pathologic response in melanoma patients.
This phase Ib trial has a multicenter, randomized design with 80 adult patients aged ≥18 years.
Patients will receive either nivolumab, ipilimumab, and/or MDNA11 or tocilizumab over a defined neoadjuvant and adjuvant regimen.
The primary endpoint is the Major Pathologic Response rate at surgery, with co-primary endpoints analyzing adverse events.
The study hypothesizes that MDNA11 will enhance clinical outcomes, aiming for a significant increase in the MPR rate.
Safety profile will be evaluated for treatment-related adverse events using CTCAE v5.0.
Quality of life and biomarker associations will also be explored.

Abstract

TPS9612 Background: Neoadjuvant immunotherapy, administered upfront of surgery in patients with resectable stage III melanoma, has shown superior efficacy in recent trials compared to post-surgical adjuvant treatment, due to enhanced anti-tumor immunity when the tumor microenvironment is intact. A pre-operative regimen of 2 cycles of ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy (as per NADINA trial) results in substantially improved event-free survival. However, even with this regimen 41% of patients did not achieve a Major Pathologic Response (MPR), with 8% having a partial pathological response and 26.4% showing pathological non-response. Previous analyses have shown a ‘cold’ CD4-IL-2 signature being associated with no-response, which could be overcome by the addition of IL-2. MDNA11 is a long-acting engineered interleukin (IL)-2 albumin fusion protein, with enhanced affinity for IL-2 receptor β (IL-2Rβ/CD122) and no binding to IL-2Rα (CD25). This design enhances the stimulation of IL-2Rβ-expressing CD8+ T cells and NK cells whilst diminishing the activation of Tregs constitutively expressing the heterotrimeric receptor containing IL-2Rα. Thus, we hypothesize that MDNA11 combination with nivolumab +/- ipilimumab may further enhance clinical outcomes of neoadjuvant standard therapy. Methods: This is a phase Ib, prospective, open-label, randomised study where a 6- week neoadjuvant phase is followed by a 7-week surgery/post-surgery phase and a 49-week adjuvant phase as per clinical practice. The study population will include adult patients of either sex aged ≥ 18 years with surgically resectable stage IIIB/C/D cutaneous melanoma. Twenty patients will be enrolled in each arm for a total of up to 80 patients. The ARM A is the control one with Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles as for NADINA trial; the ARM B includes Nivolumab 240 mg every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM C includes Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM D adds tocilizumab 4 mg/Kg on week 0 at the same schedule of the ARM C. The study’s primary endpoint is the Major Pathologic Response (MPR) rate at surgery, defined as ≤10% viable tumor in the treated tumor bed. Co-primary endpoints include the incidence, severity, and duration of treatment-related adverse events, particularly immune-related, as per CTCAE v5.0. Health-related quality of life will be analyzed using longitudinal models. Exploratory analyses will investigate biomarker associations with outcomes to generate hypotheses. Clinical trial information: 2024-519010-31-00.

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