Abstract 378TiP
Background
Glioblastoma is a poorly immunogenic cancer and is inevitably lethal despite a multimodal standard of care treatment comprising surgery followed by radiochemotherapy with temozolomide. Different immunotherapies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival. The administration of pro-inflammatory cytokines may convert the immunologically “cold” glioblastoma microenvironment into a “hot” one and may trigger potent antitumor immunity. Tumor necrosis factor (TNF) is one of the most potent pro-inflammatory cytokines. 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 fused to the antibody L19 that binds a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows targeted delivery of therapeutic doses of TNF to the tumor while sparing healthy organs. In fully immunocompetent preclinical glioma mouse models, L19TNF demonstrated promising anti-glioma activity and had encouraging synergistic activity in combination with local irradiation and temozolomide chemotherapy, providing a strong rationale to translate this treatment combination to patients with newly diagnosed glioblastoma.
Trial design
This multi-step trial has three consecutive parts: (1) a dose-finding part to determine the recommended dose of L19TNF in combination with standard temozolomide-based chemoradiotherapy for newly diagnosed glioblastoma (phase I), (2) a signal-seeking part to determine the preliminary activity for 32 patients (phase II) and (3) a 1:1 randomized activity-evaluation part that investigates the efficacy of L19TNF + chemoradiotherapy versus chemoradiotherapy alone in up to 164 patients (phase IIb). The primary endpoint of the activity-evaluation part is overall survival (OS). Eligibility criteria include histologically confirmed newly diagnosed glioblastoma with no prior therapy except surgery, a Karnofsky Performance Status (KPS) ≥ 70%, and adequate organ function.
Clinical trial identification
NCT4443010.
Editorial acknowledgement
Legal entity responsible for the study
Philogen S.p.A, Siena, Italy; Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Funding
Philogen S.p.A, Siena, Italy.
Disclosure
T. Weiss: Non-Financial Interests, Institutional, Advisory Role: Philogen. T. Hemmerle: Financial Interests, Institutional, Full or part-time Employment: Philogen. D. Neri: Financial Interests, Personal and Institutional, Stocks/Shares: Philogen. M. Weller: Non-Financial Interests, Institutional, Advisory Role: Philogen. All other authors have declared no conflicts of interest.