Diffuse midline glioma microdialysis catheter placement.
tumor, death, midline glioma, aggressive disease, midline gliomas, glioma, aggressive brain tumors, glioblastoma, intracranial U87MG
TUMOR, DISEASE, SOLID TUMORS, GLIOMA, PEDIATRIC BRAIN TUMOR, GLIOBLASTOMA
Demonstration of catheter placement in tumor tissue for timed serial extracellular fluid sampling.Within the US, midline gliomas are not routinely biopsied. However, in the last several years, using modern surgical techniques, biopsy at the time of diagnosis has been performed with acceptable risks (4% mortality rate). This will be a safety and feasibility to evaluate the pharmacokinetic and pharmacodynamic effects following administration of CDK4/6 inhibitor abemaciclib in recurrent midline glioma patients, as measured by a microdialysis catheter. We propose placement of the microdialysis catheter in midline tissue, post biopsy, to 1) assess the neuropharmacokinetic and pharmacodynamic impact of abemaciclib, 2) identify molecularly targetable alterations of tumor tissue and 3) generate PDX models for continued translational studies. Patients will be followed until death to collect information on their clinical course after protocol treatment has ended. The survival rate for these patients is usually less than 2 years from diagnosis; therefore, this is a feasible follow-up period. Detailed genomic studies post mortem have revealed the molecularly heterogeneous landscape of midline gliomas; making the selection of treatment options difficult. Previous studies through the international pediatric brain tumor consortium (PNOC) have been successful in performing biopsies on diffuse midline glioma patients to obtain tumoral genomic data for generation of personalized treatment plans, but failed to provide a survival advantage for such an aggressive disease [The doses of abemaciclib and temozolmide are expected to have an acceptable safety profile based on the experience of abemaciclib with combination dosing (150mg), per Lilly USPI, in various tumor types alone and in combination with temozolamide (200mg/m2). Additionally, there is recently opened (November 2020) Lilly clinical trial examining the combination of abemaciclib (150mg po BID) and temozolomide in young adult participants with solid tumors (including glioblastoma and midline glioma), yet no findings have been reported to date (NCT02644460). Detailed findings of combination studies with abemaciclib and temozolomide have been reported thus far in preclinical models. Raub et al detailed orally dosed abemaciclib (30-50mg/kg) significantly increased survival in a rat orthotopic U87MG xenograft rat models compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive [While small participant numbers do not allow for statistical power to detect meaningful differences in pharmacokinetic or genomic profiling, the primary objective of this study is a safety and feasibility. Once these studies demonstrate ease with safely and feasibly sampling brain extracellular fluid in midline gliomas, our intent will be to incorporate and advocate for more use of this microdialysis tool in the larger neuro-oncology field. Intent will be focused on its use in patients with cortical high grade glioma and DMG, to gain this added scientific knowledge regarding drug permeability, metabolite level variations, cytokine expression changes and other CSF biomarker detections in both adults and children with aggressive brain tumors. Too long have clinical teams relied on radiologic imaging and/or clinical exam to determine efficacy of treatment. Alternatively, these study findings will help with linking real-time pharmacokinetic and genomic profiling findings to clinical response, treatment resistance and overall patient outcomes; which will ultimately aid in advancing response predictions related to disease survivorship.