Optimizing Rhenium Re 186 Obisbemeda Dosing for Leptomeningeal Metastases
Photorealistic, artistic rendition of brain metastases - Generated with Adobe Firefly
A new dose optimization trial for rhenium Re 186 obisbemeda (Reyobiq) in patients with leptomeningeal metastases (LM) has been initiated, aiming to refine treatment regimens for this challenging central nervous system (CNS) complication.
The ReSPECT-LM dose-optimization study (NCT05034497) builds upon promising outcomes from a preceding single-dose escalation trial, moving closer to establishing a registrational trial design for this novel targeted radiotherapeutic.
“A safe and effective therapeutic to address the epidemic of CNS metastases and specifically leptomeningeal metastases is urgently needed,” said Marc H. Hedrick, MD, Plus Therapeutics president and chief executive officer, in a press release. “We expect that optimizing the dosing regimen for [rhenium Re 186 obisbemeda] in this trial will provide data needed to design and support a follow-on registrational trial.”
LM represent a severe and often rapidly progressive manifestation of advanced cancer, affecting the fluid-filled spaces surrounding the brain and spinal cord. With a median survival typically ranging from 2 to 6 months and limited effective treatment options, there is a critical unmet need for new therapeutic approaches. Rhenium Re 186 obisbemeda is a novel injectable radiotherapy designed to deliver targeted, high-dose radiation directly to CNS tumors.
Rhenium-186 is considered an ideal radioisotope for CNS therapeutic applications due to its short half-life, its emission of beta energy for effective destruction of cancerous tissue, and its gamma energy which allows for real-time imaging during treatment. This unique combination of properties supports the targeted and potent radiation delivery envisioned for rhenium Re 186 obisbemeda, aiming to reduce off-target risks and improve outcomes for patients facing the severe challenges of CNS cancers.
The dose-optimization trial is structured in alignment with the FDA’s Project Optimus initiative, emphasizing the identification of dosing regimens that maximize efficacy while ensuring patient safety and tolerability.
The primary objectives of the trial include determining the safety and tolerability of multiple doses of rhenium Re 186 obisbemeda administered via intraventricular catheter (Ommaya reservoir) at defined intervals. Furthermore, the study seeks to identify both the maximum tolerated dose and the minimum effective dose in patients with LM originating from any primary solid tumor.
Up to 24 patients will be enrolled in the study. Patients will receive rhenium Re 186 obisbemeda at the recommended phase 2 dose (RP2D) of 44.1 mCi, fractionated across 3 distinct dosing intervals. These intervals are structured into cohorts: cohort 1 at 56 days, cohort 2 at 28 days, and cohort 3a and 3b both at 14 days, with cohort 3b potentially involving up to 6 doses. The trial will assess safety profiles, pharmacokinetic and dosimetry parameters, and key efficacy-related end points. These end points include objective response rate (ORR), neurologic progression-free survival (PFS), overall survival (OS), and changes in neurologic status. The trial will also incorporate analysis of cerebrospinal fluid (CSF) tumor cell counts using Plus Therapeutics’ proprietary CNSide CSF assay platform, comparing these findings with standard CSF cytology and other pharmacodynamic markers.
This new trial follows encouraging results from the single-dose escalation study, which informed the selection of the RP2D. In that earlier trial, the 44.1 mCi dose (cohort 4) was identified as the RP2D. Pharmacodynamic and pharmacokinetic data from the single-dose study demonstrated that a single dose of rhenium Re 186 obisbemeda remained in the CSF for at least 7 days, delivering an average absorbed dose of up to 253 Gy to the cranial subarachnoid space in cohort 5.
Clinical benefit was observed in the single-dose escalation trial, with neuroimaging results showing a clinical benefit rate of 76%. Specifically, 5 of 17 patients (29%) achieved partial responses, and 8 (47%) maintained stable disease through day 112. Clinical examinations further supported these findings, with an 87% clinical benefit rate in evaluable patients, where 13 of 15 patients demonstrated a partial response or stable disease based on physician assessment. Safety data from the initial cohorts were also favorable, with no dose-limiting toxicities (DLTs) observed in the first 4 cohorts. Two grade 4 DLTs (thrombocytopenia) were reported, 1 in each of cohorts 5 and 6.
Beyond radiographic and clinical assessments, the single-dose escalation trial provided intriguing biologic insights. RNA sequencing of LM cells revealed early apoptosis, innate immune activation, and increased T-cell activity by day 28, suggesting a multifaceted antitumor mechanism. Importantly, 5 of 7 patients with over 80% reduction of LM tumor cells in CSF survived at least 1 year following initial treatment, highlighting the potential for durable responses.
Enrollment for the dose optimization trial will initially be concentrated at The University of Texas Health Science Center at San Antonio and The University of Texas Southwestern Medical Center. This focused approach aims to facilitate a rapid enrollment pace, with the potential for expansion to additional sites if necessary.
The company anticipates presenting comprehensive data and additional information from the completed single-dose escalation trial at the upcoming SNO/ASCO CNS Metastases Conference, scheduled for August 14 to 16, 2025, in Baltimore, Maryland. Following this, the company plans to request an end of phase 1 type B meeting with the FDA to align on the clinical development plan and the design of a potential registrational trial.
