Abstract OBJECTIVES Leptomeningeal metastases (LM) are an increasing complication of metastatic cancer with limited treatment options and poor survival. 186RNL is BMEDA-chelated 186Re encapsulated in nanoliposomes. 186Re’s ~2 mm beta emission path length provides direct delivery of radiation therapy while sparing surrounding healthy tissue. A Phase I dose escalation safety and efficacy study (ReSPECT-LM, NCT05034497) is current enrolling. METHODS ReSPECT-LM is a multi-center, sequential cohort, open-label, dose-escalation, Phase 1/2a clinical trial in adults evaluating the safety, tolerability, and activity of a single dose of 186RNL given via Ommaya reservoir. The primary objectives are maximum tolerated dose, safety, progression, and survival. Using a modified 3x3 Fibonacci design, increasing doses were administered in 5 mL followed by whole body planar and SPECT/CT imaging for dosimetry and distribution. CSF tumor cell count/mL using microfluidic chamber assay was assessed up to 56 days. RESULTS A total of 7 LM patients have been treated (3 male, 4 female) with metastatic oropharyngeal, breast, and lung cancer. One patient was treated twice (retreatment). 186RNL showed prompt, complete distribution throughout the CSF with durable retention in the subarachnoid space and leptomeninges. Absorbed doses ≥20 Gy to the ventricles and cranial subarachnoid spaces were measured. In patients positive for CSF tumor cells, a decrease in counts ranging from 50-92% was observed. Six patients remain alive, while 1 patient has died due to primary tumor progression. No patients had treatment related adverse events (AEs) greater than Grade 1, and the most common AE was headache. CONCLUSION Preliminary, interim results of this ongoing study showed that a single treatment with 186RNL delivered by an intraventricular catheter is well tolerated, without dose limiting toxicity and with decreased CSF tumor cell counts durable through at least 30 days. Enrollment and dose escalation is continuing, and repeated dosing will be further explored.