LMD-14. Preclinical safety and activity of intraventricular Rhenium-186 Nanoliposome ((186)RNL) for leptomeningeal metastases

INTRODUCTION: Leptomeningeal metastases (LM) is a clinical complication that occurs when cancer cells invade the leptomeninges and cerebrospinal fluid of patients with malignant tumors. Once diagnosed, limited treatment options exist, and survival is poor. Rhenium-186 Nanoliposome ((186)RNL) is a liposomal encapsulated beta emitter with a short path length of 1.8 mm, thereby allowing high specific activity brachytherapy with limited exposure to surrounding tissues. METHODS: To establish the maximum tolerated dose (MTD) of (186)RNL by intraventricular (IT) injection, eight cohorts of Wistar rats (n=3 each) were injected IT with increasing activity of (186)RNL at doses of 0 (control), 0.480, 0.800, 1.000, 1.150, and 1.340 mCi. Toxicity was assessed by daily food and water intake, daily weights, and observing for neurological deficits. To assess efficacy, C6-Luc glioma cells were injected IT and 15 days post inoculation the animals were treated with 0.69 mCi of (186)RNL. Absorbed doses were assessed with gamma camera imaging at 0h, 24h, and 48h post-treatment. Tumor growth was assessed by luciferase bioluminescence. RESULTS: No evidence of adverse (186)RNL-related effects was observed in rats through 3 months following administration of up to 1.34 mCi with an absorbed dose of up to 1075 Gy. Hence, the MTD exceeded the doses evaluated in this study. A significant difference in survival between the control and treatment groups (n=8 each) was observed at 2 weeks post treatment, with 50% survival in the control group and 100% survival in the treatment group (p=0.0087). The only significant treatment-related histologic finding among treated rats was slight focal thickening of the leptomeninges, suggesting a mild reactive hypertrophy. CONCLUSION: Intraventricular delivery of (186)RNL is well tolerated and improves animal survival at 2 weeks in a rat model of LM.