A Study With L19TNF in Combination With Lomustine in Patients With Glioblastoma at Progression or Recurrence

The present study is a randomized, open-label, non-controlled phase II study in patients with glioblastoma at any progression/recurrence (first and later).

Overall, 90 subjects will be enrolled and parallel assigned in a 1:1 fashion to one of six treatment arms (from A to F) of 15 patients each.

Each arm has a different combination of L19TNF (7 μg/kg or 10 μg/kg or 13 μg/kg) and lomustine at different dose levels (90 or 110 mg/m2).

Treatment is based on a 42-day cycle for up to a maximum of 6 cycles.

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 (1:1:1:1:1:1) to either of the six parallel treatment arms.

To maintain an appropriate balance between the six treatment arms and avoid undesired confounding effect of different factors, patients will be randomized in accordance with the following strata:

* MGMT status * Steroid administration * Previous systemic therapy treatment for progression

A randomization list will be prepared for each stratum using permuted block, the block sizes will be chosen randomly from different, pre-specified sizes with an equal treatment allocation ratio. The labels for the arms are assigned randomly within each block (fixed seed). The obtained final list is sorted by block together with the progressive enrollment number for the patients.

The primary objective of this study is to select the optimal regimen of L19TNF in combination with lomustine, that maximizes effects on clinical parameters and minimizes the probability of moderate to severe adverse events, among six (three L19TNF doses x two lomustine doses) combination schedules for the treatment of patient with progressing or recurrent glioblastoma.

Primary endpoints include Safety (Incidence of adverse Events (AEs), Serious Adverse Events (SAEs) and Drug-Induced Liver Injury (DILI), standard laboratory assessments, ECG, ECHO and physical examination according to CTCAE v.5.0) and Efficacy (Survival rate at 12 months).

The secondary objective of this study is to further evaluate safety, efficacy, exposure, dose-response, pharmacokinetic and pharmacodynamic information of the combination of L19TNF and lomustine at different dose levels to determine the best dose regimen for further studies.