ACTR-33. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

Abstract

Local delivery into the central nervous system circumvents the challenges associated with the blood-brain barrier and minimizes systemic toxicity while achieving higher concentrations of therapeutics. Convection enhanced delivery (CED) utilizes fluid convection to distribute macromolecules into the interstitial spaces of brain parenchyma. CED a high-concentration version of liposomal irinotecan (nal-IRI-HC) has been optimized in animal models and showed promising anti-tumor activity. A major recent advance in the application of CED is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor infusions and ensure precise delivery. A phase I study is ongoing evaluating CED of nal-IRI-HC with real-time MRI for patients with recurrent high grade glioma (HGG). This 3+3 dose escalation trial employs dose levels of 20 mg, 40 mg, 60 mg, and 80 mg of nal-IRI-HC, given via up to 3 catheters surgically placed in an intra-tumoral location. Maximum total volume infused will be 1.0 ml for the two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. To date 7 patients have been enrolled and treated. Median progression free survival was 2.9 months. All radiographic progression was found to be outside the infusion area. One grade 3 adverse event was encountered. The median total volume of distribution (Vd) to volume infused (Vi) ratio was 1.6 - 2.0 for each infusion based on correlations between pre-infusion modeling of drug distribution and post-infusion imaging. Image-guided CED allows for real-time placement and adjustment of cannula and for real time visualization of therapeutics into the brains of patients with recurrent HGG. In this early phase trial, real time CED of nal-IRI-HC appears well tolerated and suggests larger volume infusions warrants clinical evaluation.