Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients

Summary

Objectives

The present study is an open-label, randomized, controlled, two-arm multi-center study of
the efficacy of Daromun neoadjuvant intratumoral treatment followed by surgery and
adjuvant therapy versus surgery and adjuvant therapy in clinical stage III B/C melanoma
patients. 186 patients will be randomized in a 1:1 ratio to receive Daromun treatment
followed by surgery and adjuvant therapy (Arm 1) or surgery and adjuvant therapy (Arm 2).

In both arms, follow-up for assessing recurrence-free survival will be performed up to
five years after randomization. Survival information will also be collected in the
following year (up to six years in total after randomization).

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

Patients who successfully complete the screening evaluations and are eligible for
participation in the study will be enrolled and randomly assigned (1:1) to two parallel
treatment arms: Daromun plus surgery and adjuvant therapy (Arm 1) or surgery and adjuvant
therapy (Arm 2).

To ensure a balance across treatment groups, stratified randomization with permuted block
will be used and separate randomization list for each subgroup (stratum) will be
produced. Patients will be stratified on the basis of the following prognostic factors:

- Stage of disease (2 levels): Stage IIIB vs. Stage IIIC

- Planned post-surgical adjuvant therapy (2 levels): anti-PD-1 and other adjuvant
therapies.

The primary objective of the study is to demonstrate that a neoadjuvant Daromun treatment
followed by surgery and adjuvant therapy improves in a statistically significant manner
the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the
standard of care (surgery and adjuvant therapy).

Primary endpoint of the study is RFS in a time-to-event analysis in the Daromun plus
surgery and adjuvant therapy treatment group (Arm 1) versus the surgery plus adjuvant
therapy control group (Arm 2). Analysis will be based on the "Intention To Treat"
population.

The key secondary objective of the study is to demonstrate that a neoadjuvant Daromun
treatment followed by surgery and adjuvant therapy improves in a statistically
significant manner the overall survival (OS) of patients with resectable Stage IIIB/ or C
melanoma patients with respect to the standard of care (surgery and adjuvant therapy).

For patients enrolled in both arms, local approved post-surgery adjuvant therapies (as
part of the standard of care) are allowed and decided at the investigator's discretion.
These include high-dose interferon- a2b, anti-CTLA-4 antibodies (e.g. Ipilimumab),
anti-PD1 antibodies (e.g. Nivolumab, Pembrolizumab), targeted therapies (e.g. Dabrafenib
+ Trametinib), or other new local approved treatments.