Study of the Efficacy of Intratumoral L19IL2 or L19TNF or L19IL2/L19TNF, in Combination with Pembrolizumab, in Unresectable Melanoma Patients

The present study is a randomized, open-label, three-arm, parallel phase 2 study. A Simon two-stage design for the study of the efficacy of intralesional therapy with L19IL2 or L19TNF or L19IL2/L19TNF in combination with systemic anti-PD1 pembrolizumab immunotherapy will be used.

In the study, 162 patients will be randomized in a 1:1:1 ratio to receive:

i) systemic pembrolizumab in combination with intralesional L19IL2 (Arm 1) or ii) systemic pembrolizumab in combination with intralesional L19TNF (Arm 2) or iii) systemic pembrolizumab in combination with intralesional L19IL2/L19TNF (Arm 3).

This is an open-label study, so there is no blinding.

The study consists of a two-week screening period, followed by a 4-weeks open-label intralesional treatment period with immunocytokines (ICKs) either L19IL2, L19TNF or L19IL2/L19TNF. Pembrolizumab will be administered by i.v. infusion on the first day of intralesional treatment with ICKs, and will continue every 3 weeks for approximately 2 years, 35 cycles, 2 year cap or until disease progression or unacceptable toxicity, whichever comes first.

Follow-up for progression free survival will be performed up to 2 years after first intralesional treatment. Survival information will be collected up to 3 years after first intralesional treatment.

A safety run-in will be performed on the first 12 patients enrolled in each arm of the study. Patients will be evaluated during the first 21-days cycle for the occurrence of the treatment-related adverse events. All toxicities will be graded using NCI CTCAE Version 5.0 based on the investigator assessment to be possibly, probably, or definitely related to study treatment administration.

In addition to this, safety information collected will be routinely reviewed by the Data and Safety Monitoring Board (DSMB) in order to identify possible safety concerns.

The primary objective of the study is to demonstrate the efficacy of intralesional treatment with ICKs, in combination with systemic anti-PD1 immunotherapy with pembrolizumab, to induce objective responses in advanced melanoma patients with resistance to or progressing upon anti-PD1 checkpoint inhibitors.

Primary endpoint of the study is the Confirmed Objective Response Rate (ORR = CR + PR) in all three arms over a period of up to 2 years after first intralesional treatment, according to RECIST v1.1 criteria in each arm of the study. The primary analysis will be performed in the Intention-to-Treat population (ITT).