Neoadjuvant L19IL2/L19TNF- Pivotal Study

Phase III, open-label, randomized, controlled multi-center study. In the study, 214 patients will be enrolled and parallel assigned (via automated randomization system) in a 1:1 fashion to one of two different arms: ARM 1: Patients in Arm 1 will receive multiple intratumoral administrations into all injectable cutaneous, subcutaneous, and nodal tumors of a mixture of L19IL2 and L19TNF once weekly for up to 4 weeks (or until all injectable tumors have disappeared, or intolerance to study treatment or in the opinion of the investigator immediate surgical resection or any other treatment for melanoma is warranted, whichever occurs first). The whole volume of L19IL2/L19TNF will be distributed among all injectable lesions. Newly occurring injectable melanoma lesions within the 4 weeks treatment period will also be treated as described. For the new lesions the treatment period will not be extended beyond the pre-defined 4 week- treatment period with a clock start at the time of the first intralesional L19IL2/L19TNF injection. Surgical resection of all existing metastases will follow within 4 weeks after end of treatment. Surgery will be performed after the safety evaluation carried out at week 5 and, if indicated, may be carried out on the same day of the safety evaluation. Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician. ARM 2: Patients in Arm 2 will receive directly surgical resection of melanoma tumor lesions within 4 weeks after randomization. Post-surgery EMA-approved adjuvant therapy is allowed at discretion of the treating physician. Patients will be followed on a regular basis for the primary outcome until 36 months from randomization and up to 60 months for overall survival. Expected patient enrollment interval: 60 months. Duration of individual patient's participation: up to 60 months. End of treatment corresponds to the day of surgery for patients randomized to both Arm 1 and Arm 2. End of study corresponds to the last patient last visit (LPLV). The final primary efficacy analysis will be conducted when the 95th recurrence event is observed.