Rhenium Obisbemeda Demonstrates Safety and Feasibility in Leptomeningeal Metastases

Treatment with up to 44 mCi of intrathecal rhenium (186Re) obisbemeda (rhenium nanoliposome, 186RNL) was shown to be feasible and safe, with high absorbed radiation doses and high mean circulating tumor cell reductions in patients with leptomeningeal metastases, according to interim findings from the phase 1 ReSPECT-LM trial (NCT05034497).¹

Among the 16 patients who were included in the safety and efficacy report, 8 had breast cancer, 4 had lung cancer, and the rest (n = 4) had a mix of other primary cancers. The median overall survival (OS) for these patients who had been enrolled in cohorts 1 through 4 was 12 months with 8 of 16 patients alive at the time of analysis.

“The ReSPECT-LM phase 1 dose escalation study continues to show feasibility, safety, and a response in circulating tumor cells in patients [with] leptomeningeal metastases treated with rhenium obisbemeda,” Andrew Brenner, MD, PhD, a professor and Kolitz/Zachry Endowed Chair of Neuro-Oncology Research and co-leader of the Experimental and Developmental Therapeutics Program, at the University of Texas Health, San Antonio, stated in the news release. “Furthermore, a median OS of 12 months is very encouraging and is consistent with the high doses of absorbed radiation delivered and the mean circulating tumor cell reduction we have observed.”

Leptomeningeal disease, which occurs when cancer spreads to the cerebrospinal fluid and leptomeninges around the brain and spinal cord, is common in solid tumors, primary brain tumors, and hematologic malignancies. Moreover, the incidence of leptomeningeal disease is increasing due to longer cancer survival and the inability of standard chemotherapies to effectively reach the cerebrospinal fluid. There are currently no FDA-approved treatments for leptomeningeal disease.

186RNL is designed to deliver targeted, high-dose radiation directly to central nervous system (CNS) tumors, offering a potent and precise radiation dose, potentially reducing off-target risks and improving outcomes. The drug is beneficial for CNS treatments due to its short half-life, cancer-destroying beta energy, and gamma energy for real-time imaging.

Previously the FDA granted an orphan drug designation to the novel, injectable radiotherapy as a potential therapeutic option for patients with breast cancer and leptomeningeal metastases.^1,2

Patients 18 years of age or older with leptomeningeal metastases from their primary cancer are eligible for enrollment in ReSPECT-LM, excluding those with two-dimensional leptomeningeal metastases. Eligibility criteria mandate that patients have a Karnofsky performance status between 60 and 100, acceptable liver function, adequate renal function with serum creatinine up to 2 times the upper limit of normal, and adequate hematologic status.³

Exclusion criteria include unresolved adverse effects (AEs) from prior treatments, obstructive or symptomatic communicating hydrocephalus, non-programmable ventriculo-peritoneal or ventriculo-atrial shunts, serious intercurrent illness, and previous radiation to the spinal cord or whole brain (non-CNS radiation to the primary tumor is allowed). Systemic chemotherapy with CNS penetration is not permitted within 14 days or 5 half-lives before the study treatment.³

Additional results illustrated a linear increase in absorbed radiation dose to the spinal fluid, ventricles, and cranial subarachnoid space across the 4 cohorts. In cohort 4, the mean absorbed radiation dose was 156 Gy in the ventricles and cranial subarachnoid space compared with 1 Gy in the spleen. Additionally, a 53% mean reduction in cerebrospinal fluid circulating tumor cells was observed in cohorts 1 through 3 28 days post-treatment compared with baseline. Circulating tumor cells were only measured in cohorts 1 through 3 due to commercial unavailability of testing during cohort 4.¹

It was also shared that the maximum-tolerated dose or maximum feasible dose of the agent was not reached. There were also no dose-limiting toxicities through cohort 4. Most AEs across all cohorts were mild or moderate and were unrelated or unlikely related to the study drug.¹

The phase 1 trial is currently enrolling patients for cohort 5. 186RNL is also being evaluated in the phase 1/2 ReSPECT-GBM trial (NCT01906385) in patients with recurrent glioblastoma.^1,2

References

1. Plus Therapeutics presents positive interim ReSPECT-LM phase 1 data for leptomeningeal metastases at 2024 SNO/ASCO CNS Metastases Conference. News release. Plus Therapeutics. August 12, 2024. Accessed August 12, 2024. https://ir.plustherapeutics.com/news-releases/news-release-details/plus-therapeutics-presents-positive-interim-respect-lm-phase-1
2. Plus Therapeutics granted US FDA orphan drug designation to rhenium (186Re) obisbemeda for the treatment of breast cancer with leptomeningeal metastases. News release. Plus Therapeutics. November 3, 2023. Accessed August 12, 2024. https://ir.plustherapeutics.com/news-releases/news-release-details/plus-therapeutics-granted-us-fda-orphan-drug-designation-rhenium
3. Intraventricular administration of rhenium-186 nanoliposome for leptomeningeal metastases (ReSPECT-LM). ClinicalTrials.gov. Updated July 30, 2024. Accessed August 12, 2024. https://clinicaltrials.gov/study/NCT05034497