Leptomeningeal Metastases


Leptomeningeal Metastases

Leptomeningeal Metastases (LM) are a rare, difficult-to-treat, late-stage, devastating cancer complication in which cancer cells spread to the central nervous system (CNS) and are found in either the leptomeninges (membrane surrounding the brain and spinal cord) or cerebrospinal fluid (CSF) (circulates nutrients and chemicals to the brain and spinal cord).

LM are diagnosed in ~5% of patients with metastatic cancer, but are often undiagnosed or asymptomatic and, at autopsy, the frequency of LM is 20%.  LM most commonly spread from 4 primary cancers:  breast cancer (12-35%), lung cancer (10-26%), melanoma (5-25%), and gastrointestinal cancer (4-14%).  The annual incidence of people diagnosed with LM is rising due to improved diagnostic neuroimaging and primary cancer treatments that improve survival.

LM negatively impacts a person’s quality of life by causing neurological complications such as difficulty thinking, double vision, and headaches.  The reported survival for patients diagnosed with LM is 7% at 1 year and 3% at 3 years with a mean of 2 to 4 months.

“Leptomeningeal metastases are a fatal complication of advanced cancer and despite affecting more than 110,000 people per year in the United States alone, there remains a significant lack of effective therapies to treat this devastating disease,” said Andrew J. Brenner, M.D., Ph.D., Professor of Medicine, Neurology, and Neurosurgery at The University of Texas.

Standard Treatment for Leptomeningeal Metastases

The goals in treating LM are to improve survival and maintain quality of life by delaying neurological deterioration.  Standard treatment includes radiation therapy to the affected sites (i.e. meningeal nodules) followed by chemotherapy, given either orally, intravenously, or directly into the CSF (intrathecal or intra-Ommaya).  
Poor-risk (low KPS) LM patients typically receive a palliative regimen including whole body radiation therapy, analgesics, corticosteroids, anticonvulsants, ventriculoperitoneal shunting, and stimulants.  On the other hand, good-risk (high KPS) LM patients’ treatment is focused on tumor control using focal radiation therapy to treat bulky or symptomatic areas, intrathecal chemotherapy (methotrexate, cytarabine) or systemic chemotherapy (methotrexate, cytarabine, capecitabine, targeted therapies).
The risk of significant side effects from entire neuraxis radiation therapy generally outweighs the benefits in this relatively radioresistant tumor; focal radiation therapy relieves neuro symptoms but has no significant effect on survival.
Due to the relatively short median survival, a careful weighing between prolonging life while worsening the quality of life and maintaining the pain‐free quality of life without prolonging life needs to be discussed and evaluated with the patient.


While external beam radiation therapy (EBRT) is used for the treatment of LM, the dose is limited due to potential CNS toxicity with craniospinal radiation falling out of favor due to poor tolerance.  We hypothesize that, given the short path length and favorable radiation properties of 186RNL, intraventricular treatment via Ommaya reservoir will be safe at markedly higher doses than conventional EBRT, leading to better survival.

A preclinical study was conducted to investigate the maximum tolerable dose (MTD), safety, and efficacy of 186RNL in rat models of LM.

Maximum Tolerable Dose (MTD)

5 different 186RNL doses were tested in non-tumor bearing rats.  No overt neurological symptoms were deteded in any rats after 186RNL injection for the duration of the 4 week experiment.  Rats administered with the highest doses presented minimal weight loss after the first week after surgery but gained it back in subsequent weeks.  This suggests that the maximum tolerable dose was not reached.

Glioma LM Rat Model

Wistar rats were injected with glioma cells and then injected with either empty nanoliposomes or 186RNL.  The results showed a statistically significant difference in overall survival, with the 186RNL-treated animals outliving the nanoliposome-treated animals (control).

Breast Cancer LM Rat Model

Female RNU rats were inncoulated with breast cancer cells and then injected with either empty nanoliposomes or 186RNL.  The results showed a statistically significant difference in tumor burden beginning 6 days after treatment that reached 10-fold by 2 weeks post-treatment when nanoliposome-treated (control) animals began expiring.

The ReSPECT™-LM Phase 1 clinical trial follows preclinical studies in which tolerance to mean doses of 186RNL of 1,094 Gy were shown in LM rat models with no observed significant toxicity and treatment led to marked reduction in tumor burden in both glioma and breast cancer LM rat models.



In the U.S. multi-center ReSPECT-LM Phase 1 clinical trial, a radiotherapeutic called 186RNL (Rhenium-186 NanoLiposome) will be administered through an intraventricular catheter (Ommaya reservoir) in patients with leptomeningeal metastases.  The treatment consists of a single administered, 5 cc dose of 186RNL per patient on an outpatient basis by the clinical trial physician.  The trial will include the evaluation of 3 separate dose levels and 3 to 6 patients may be treated at each dose.  The maximum number of patients to be enrolled in the study is 18.

An Ommaya reservoir is a device that is placed under the scalp and connected to a catheter that is placed in one of the ventricles of the brain.  Credit:  P. Lynch

Visit ReSPECT-Trials.com to learn more.

The U.S. Food and Drug Administration (FDA) has not approved 186RNL for this specific disease.  


In the second quarter of 2021, the Company received a positive response to the 186RNL pre-IND (Investigational New Drug) meeting briefing package that it submitted in the first quarter of 2021 to the U.S. FDA for the treatment of leptomeningeal metastases (LM).

The Company received U.S. FDA IND clearance for 186RNL for leptomeningeal metastases in October 2021 and plans to begin the ReSPECT-LM Phase 1 clinical trial by the end of 2021.  To learn more, click here.