Glioblastoma is the most aggressive primary brain tumour in adults with a dismal prognosis and median overall survival of 12–14 months despite standard therapy. Novel discoveries in Cancer Neuroscience have revealed excitatory neuron-to-tumour synapses that drive glioma proliferation and invasion via AMPA-receptor activation, and vital tumour-autonomous calcium signalling mediated by KCa3.1 channels that sustain cancer cell network- and therapy resistance. Both mechanisms have been effectively targeted in preclinical studies using perampanel, a non-competitive AMPA-receptor antagonist, and senicapoc, a selective KCa3.1 blocker, suggesting promising avenues for treatment. This trial was designed to test the safety, pharmacokinetics, and biological effects of these drugs, as mono- and combination therapy, when added to standard-of-care treatment in newly diagnosed glioblastoma. SENIPERA is a two-stage, phase 0/1, prospective, open-label, randomised clinical trial with an exploratory window-of-opportunity design. A total of 27–36 adult patients with newly diagnosed glioblastoma will be enrolled. Trial Part A will enrol 9–18 patients in a 3 + 3 dose-escalation design to determine the maximum tolerable dose (MTD) of senicapoc. In Part B, 18 patients will be randomised 1:1 to receive perampanel monotherapy or combination therapy with senicapoc at the established MTD. Study treatment begins upon enrolment 7–14 days before surgery and continues until 30 days after adjuvant radiochemotherapy. Primary endpoints are the MTD of senicapoc (mg) (Part A) and the proportion of patients discontinuing perampanel due to intolerance at the lowest dose (Part B). Secondary endpoints include safety parameters, overall and progression-free survival, objective response rate, and tumour-volume changes. Exploratory analyses will characterise pharmacokinetics, tumour drug penetration, and molecular- genetic tumour profiles. SENIPERA introduces a dual network-targeting strategy that simultaneously addresses neuronal-driven invasion and tumour network resilience in glioblastoma. By integrating senicapoc and perampanel with standard therapy in an early-phase, window-of-opportunity design, this study will establish the preliminary safety and pharmacological foundation for future trials evaluating safety and efficacy. The comprehensive translational analyses of tissue, cerebrospinal fluid, and blood will provide detailed insight into drug activity within the tumour microenvironment, informing the development of potential biologically guided treatment strategies for glioblastoma. EU-CT: 2025–522605-37–00. Trial sponsor. Aarhus University Hospital. Department of Neurosurgery, Palle Juul-Jensens Boulevard 165, J617. Aarhus, Denmark. Protocol version and date. Version 1.0 November 26, 2025.
Eschen et al. (Tue,) studied this question.
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