Introduction Inadequate delivery is a central cause for drug development failure in neuro-oncology. Intra-arterial drug infusion for brain tumors was first proposed in 1962. Derivatives of this approach have been explored in 20 clinical trials, yet no study has quantified blood-brain barrier penetration. We report the first Phase 0 clinical trial of superselective intra-arterial infusion (SSIAI), examining tissue pharmacokinetics (PK) and pharmacodynamics (PD) of the mTOR inhibitor temsirolimus in recurrent glioblastoma.
Methods Patients receive one dose of temsirolimus prior to planned tumor resection. As part of our modified SSIAI protocol, a microcatheter is navigated under fluoroscopic roadmap techniques through the distal vasculature in proximity to the tumor. In dose-escalation cohorts, temsirolimus (5mg vs. 15mg) or mannitol (12.5mL vs. 25mL) varies. In time-escalation cohorts, the interval from SSIAI to tissue acquisition (4hrs vs. 8hrs) varies. Drug concentration is quantified in blood, cerebrospinal fluid, and gadolinium-enhancing and non-enhancing tumor tissue. S6 phosphorylation is quantified to interrogate mTOR modulation.
Results Accrual is ongoing, but no adverse events were observed in the first patient. Four hours post-SSIAI (5mg temsirolimus), total drug concentration in enhancing tumor was 1045 nM. In comparison, 250mg of IV temsirolimus was previously reported to yield 225 nM. SSIAI of temsirolimus decreased tumor pS6 levels from baseline.
Discussion Using a modified SSIAI protocol, the efficiency of temsirolimus penetration into gadolinium-enhancing glioblastoma tissue was augmented nearly 250-fold. In comparison to IV administration, SSIAI minimizes dose (5mg vs. 250mg), maximizes total drug (1045 nmol vs. 225 nmol), and limits side effects related to systemic exposure. PK-/PD-driven studies are necessary to optimize SSIAI in brain tumors.
Disclosures F. Albuquerque: None. N. Sanai: 1; C; Ben and Catherine Ivy Foundation. J. Hartke: None. J. Baranoski: None. K. Hendrickson: None. J. Harmon: None. A. Tien: None. S. Mehta: None. A. Tovmasyan: None. A. Ducruet: None.
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