This is an open-label, multicenter, Phase 1 study to determine the safety and efficacy of multiple doses at defined intervals of rhenium (186Re) obisbemeda (rhenium-186 nanoliposome, 186RNL) administered via intraventricular catheter for any primary solid tumor cancer with leptomeningeal metastases to identify an MTD/MFD for a given dose, interval duration, and number of doses.
At least 18 years of age.
Ability to understand the purposes and risks of the study and has signed a written informed consent document approved by the site-specific IRB.
Documented LM from any primary solid tumor cancer per EANO-ESMO Clinical Practice Guidelines (Types I or IIA-C).
Karnofsky performance status of 70 to 100.
The subject has not recovered to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0) Grade ≤1 from adverse events (AEs) due to antineoplastic agents, investigational drugs, or other medications that were administered prior to study, at time of study registration.
Contraindications to the placement of an intraventricular catheter (i.e., Ommaya reservoir.)
Presence of or need for a Ventriculo-peritoneal or ventriculo-atrial shunt.
Females of childbearing potential who are pregnant, breastfeeding, or may possibly be pregnant, without a negative serum pregnancy test (see inclusion criteria).
Sequential
186RNL
DrugMultiple Doses of 186RNL
Maximum Tolerated Dose
Evaluation of any toxicity associated with research treatment per Common Criteria for Adverse Events.
Dose Distribution of 186RNL
SPECT imaging of the radioactive materials spread in the Cerebrospinal Fluid.
Safety and tolerability of multiple dose treatment
Evaluation of any toxicity associated with research treatment as determined by National Cancer Institute (NCI) common Terminology Criteria for adverse events (CTCAE).
Determine the objective response rate (ORR).
Determine the overall response rate (ORR) defined as the proportion of all evaluable participants achieving a response as the best overall response at the time of progression.
Determine the overall survival (OS).
The time from first treatment to date of death.
Characterize the dosimetry profile of 186RNL.
using the following equation to calculate the average radiation-absorbed dose in the CSF Volume (Eckerman and Endo 2008): D (Gy) = 7.126 (Gy.g/mCi.h) × A cummu. (mCi.h)/ m (g) D is the average radiation-absorbed dose in Gy. A cummu. is the cumulative radioactivity in mCi.h calculated as described above. m is the weight of the radioactivity distribution volume in grams. Given that there is no specific tumor mass to use for organ mass in grams identifiable post-infusion, the Sponsor proposes to use the estimated total CSF volume to calculate the absorbed dose to the CSF. To perform radiation-absorbed dose calculation, the weight will be calculated from the average CSF volume (Adult Male: 140 ml; Adult Female: 120 ml), assuming the density of 1 g/cm3.
Determine neurologic progression-free survival (PFS).
The time from first treatment to progression.
Exploratory: Assess response using CSF tumor cell enumeration and compare to standard of care cytology.
Comparing the diagnostic accuracy of CNSide (cell capture and ctDNA) with cytology in diagnosing and monitoring LM and will be described in terms of sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) (as appropriate statistically).
Exploratory: Assess response using pharmacodynamic (PD) markers.
Determination of DNA damage markers by regression analyses of the time-activity curves will be performed and the residence times of 186RNL in red marrow will be computed using a reduction factor of 0.3 to consider the difference in activity between blood and marrow.
Safety: Determination of the incidence and severity of adverse events (AE) and serious adverse events (SAE).
Safety will be evaluated by the incidence of AEs and SAEs graded according CTCAE version 5.0
Safety: Determination of the incidence of dose limiting toxicities (DLT).
Maximum Tolerated Dose (MTD) will be evaluated by testing increasing doses with 3 to 6 participants in each cohort. MTD reflects the highest dose of drug that did not cause a Dose Limiting Toxicity (DLT) in \> 33% of participants.
