Senicapoc and Perampanel for Newly Diagnosed Glioblastoma

The primary endpoint of the study's Part A will be the maximum tolerable dose of senicapoc monotherapy (milligrams, first four weeks) when added to standard-of-care therapy.

The primary endpoint of Part B is the number of patients in each group (2 and 3) excluded from the study due to intolerability when exposed to perampanel at the lowest dose (2 mg) within the first 6 weeks of treatment.

Safety will be measured as the risk of adverse events and serious adverse events in each group, evaluated continuously from inclusion until ~30 days after patient exclusion, graded by Common Terminology Criteria for Adverse Events version 5.0 and tabulated by type, grade, and attribution.

Overall survival is defined as the time from randomization to death from any cause. Patients still alive at End-of-trial or lost to follow-up will be censored at the date of last contact. End-of-trial is defined as 1 year after the last patient completes treatment in Part B, with an estimated maximum follow-up of approximately 24 months per participant.

Progression-free survival is defined as the time from randomization to first documented disease progression according to RANO 2.0 criteria or death from any cause, whichever occurs first. Patients without progression or death at End-of-trial or lost to follow-up will be censored at the date of last contact. End-of-trial is defined as 1 year after the last patient completes treatment in Part B, with an estimated maximum follow-up of approximately 24 months per participant.

Objective response rate is defined as the proportion of patients achieving complete or partial response according to RANO 2.0 criteria. Response is assessed relative to the postoperative baseline MRI obtained within 48 hours after surgery. Patients without a documented response at End-of-trial or lost to follow-up will be censored at the date of last contact. End-of-trial is defined as 1 year after the last patient completes treatment in Part B, with an estimated maximum follow-up of approximately 24 months per participant.

Tumor volume will be quantified based on manual or semiautomated segmentation of T2 FLAIR hyperintense and T1 contrast-enhancing lesions. Preoperative tumor volumes obtained approximately on day 10-14 will be compared to baseline postoperative MRI volumes obtained within 48 hours after surgery. Postoperative tumor volumes assessed on follow-up MRIs will be compared to this postoperative baseline. Aggregated volumes and volume changes compared to baseline will be reported for each time-point.

In Part B, the mean maximum tolerated daily dose of perampanel achieved during the first six weeks of treatment will be recorded for each participant and compared between groups 2 (perampanel monotherapy) and 3 (perampanel + senicapoc).

Cmax of senicapoc measured in serial blood samples using validated UHPLC-MS/MS methods. Samples are collected at predefined visits throughout the treatment period

Cmax of perampanel measured in serial blood samples using validated HPLC-MS methods. Samples are collected at predefined visits throughout the treatment period.

AUC of senicapoc measured in serial blood samples using validated UHPLC-MS/MS methods. Samples are collected at predefined visits throughout the treatment period.

AUC of perampanel measured in serial blood samples using validated HPLC-MS methods. AUC will be estimated using non-compartmental analysis based on predefined serial blood sampling throughout the treatment period.

Elimination half-life (t½) of senicapoc estimated from serial blood concentrations using validated UHPLC-MS/MS methods and non-compartmental pharmacokinetic analysis.

Elimination half-life (t½) of perampanel estimated from serial blood concentrations using validated HPLC-MS methods and non-compartmental pharmacokinetic analysis.

CSF concentrations of senicapoc and perampanel measured using validated analytical methods. CSF samples are collected at predefined postoperative time points and compared with plasma levels.

Concentrations of senicapoc and perampanel in tumor tissue and peritumoral brain tissue obtained during surgery and quantified using validated analytical methods. Tissue concentrations will be compared with matched plasma and cerebrospinal fluid levels.

MGMT-promotor methylation status evaluated from resected tumor tissue.

CHI3L1-conductivity score evaluated from resected tumor tissue.

Neural epigenetic signatures evaluated from resected tumor tissue.

Proportions of glioblastoma cellular subtypes (NPC-like, OPC-like, MES-like, AC-like) will be quantified using single-cell RNA sequencing of tumor core and peritumoral tissue obtained at surgery. Subtype proportions will be compared between treatment groups.

Differential gene expression profiles in tumor core and peritumoral tissue will be quantified using single-cell RNA sequencing. Differential expression analysis will compare treatment groups and tissue regions using generalized linear mixed models.

Expression levels of predefined transcriptional signatures associated with treatment resistance will be quantified using single-cell RNA sequencing and spatial molecular imaging. Gene Set Enrichment Analysis (GSEA) will be used to identify signature enrichment in tumor core and peritumoral regions.