SYST-03. A PHASE I/II STUDY TO EVALUATE SAFETY AND PRELIMINARY ACTIVITY OF THE TUMOR-TARGETING ANTIBODY-CYTOKINE FUSION PROTEIN L19TNF IN PATIENTS WITH GLIOBLASTOMA AT FIRST RELAPSE

Abstract

Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. We previously demonstrated encouraging anti-tumor activity with the targeted delivery of tumor necrosis factor a (TNF) in preclinical orthotopic glioma models. TNF- a is a potent pro-inflammatory cytokine which may trigger strong anti-tumor immunity. However, its systemic administration at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising TNF- a fused to the antibody L19 that binds a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site upon intravenous administration while sparing healthy tissues. In this phase I/II open label, non-randomized, monocentric study, we investigated the safety and preliminary activity of L19TNF for patients with isocitrate dehydrogenase (IDH) wildtype World Health Organization (WHO) grade III / IV glioma at first relapse. Twenty patients were enrolled from 2019-2020 and treated with intravenous infusions of L19TNF. In the phase I part of the study, 6 patients were assigned to two different dose levels of L19TNF and a dose of 13 µg/kg was established as the recommended dose. In the phase II part 14 patients were treated at the recommended dose. No dose-limiting toxicities were observed and survival follow-up is ongoing. In almost all patients, we observed treatment-associated emerging tumor necrosis. For patients that had re-surgery at progression on or after treatment with L19TNF, we demonstrated increased numbers of tumor-infiltrating lymphocytes compared to the tumor tissue obtained at primary diagnosis. Translational studies to better understand the effects of L19TNF on a molecular and immunophenotypic level are ongoing. ClinicalTrials.gov Identifier: NCT 03779230