Rhenium (186Re) Obisbemeda (186RNL) in Leptomeningeal Metastases Phase 1 Dose Escalation Trial: Update for Initial Safety, Feasibility and Preliminary Efficacy

Rhenium (186Re) Obisbemeda (186RNL) in Leptomeningeal Metastases

Phase 1 Dose Escalation Trial: Update for Initial Safety, Feasibility and Preliminary Efficacy

Andrew Brenner1, Michael Youssef2, Priya Kumthekar3, Joel Michalek1, Marc Hedrick4, Melissa Moore4, Ande Bao5,

WilliamPhillips1, Toral Patel2, JeffreyWeinberg6, John Floyd1, Norman LaFrance4

1UT Health San Antonio Mays Cancer Center, 2UT SouthwesternMedical Center, 3Northwestern University, 4Plus Therapeutics, 5Case Western Reserve University, 6MD Anderson Cancer Center

INTRODUCTION

Rhenium (186Re) obisbemeda (186RNL), a next generation radiotherapeutic, is BMEDA-chelated186Re encapsulated in liposomal nanoparticles. 186Re is a beta- emitting therapeutic radionuclide with a 90-hourhalf-life, ~2 mm tissue path length, and optimal 137 keV γ-decay that allows real-time imaging of in vivo drug distribution by SPECT/CT.

Leptomeningeal metastasis (LM) is a devastating cancer of the CSF and membranes surrounding the brain and spinal cord, diagnosed in approximately 5- 15% of all cancer patients. Typical treatment strategies include optimal systemic therapy for the primary disease, as well as neuroaxis-directed therapy, which may include intrathecal chemotherapy or radiotherapy. External Beam Radiation Therapy (EBRT) is limited to ~30-50 Gray (Gy) over multiple fractions to limit toxicity including myelopathy and marrow suppression given the dose to the brain, spinal cord, and surrounding tissues. With treatment, median overall survival is 2-6 months; without treatment, 4-6 weeks.

Durable, localized treatment with beta emitters has the potential to dramatically widen the therapeutic window, increase the delivered dose, avoid normal tissue exposure, and extend survival in patients with LM. 186RNL uses Direct Targeted Delivery, which deposits high doses of radiation non-systemically and locoregionally to achieve thorough tumor coverage and retention with high absorbed radiation doses. For LM, 186RNL is infused via Ommaya reservoir (intraventricular catheter) (Figure 1).

Figure 1. 186RNL is BMEDA-chelated

186Re encapsulated in nanoliposomes. For the treatment of LM, it is directly delivered to the CSF via intraventricular catheter (Ommaya reservoir).

STUDY DESIGN

ReSPECT-LM is a multi-center, sequential cohort, open-label,dose-escalation, Phase 1 clinical trial to evaluate the safety and tolerability of a single dose of 186RNL given by the intraventricular route (Ommaya reservoir) in adult patients with LM from any primary cancer. The primary objective of the Phase 1 study is to determine a maximum tolerated dose (MTD)/maximum feasible dose (MFD) over 7 cohorts utilizing a modified 3+3 Fibonacci design (Table 1).

Cohort	Infused	Total 186RNL	Concentration	Increase	Status
Volume (mL)	Activity (mCi)	(mCi/mL)
1	5	6.6	1.32	N/A	Complete
2	5	13.2	2.64	100%	Complete
3	5	26.4	5.28	100%	Complete
4	5	44.10	8.82	67%	Complete
5	5	66.14	13.23	50%	Enrolling
6	5	87.97	17.59	33%	Pending
7	5	109.96	21.99	25%	Pending

Table 1. ReSPECT-LM dose escalation schema for cohorts 1-7. Cohort 5 is currently enrolling.

The starting dose level of 6.6 mCi (Cohort 1) was based on results of preclinical studies. Patients included on study are at least 18 years of age, have proven and documented LM (EANO-ESMO Clinical Practice Guidelines Type 1 and 2, except for 2D), Karnofsky performance status of 60-100, and standard organ function. As noted above, patients with any primary cancer are included. Patients with obstructive or symptomatic communicating hydrocephalus, ventriculo-peritoneal or ventriculo-atrial shunts without programable valves, contraindications to placement of Ommaya reservoir, any prior radiation dose to the spinal cord or whole brain radiation therapy, or standard concomitant illnesses are excluded from the study.

Because 10-70% of subjects with LM have some sort of CSF flow abnormality, all study participants require a diagnostic CSF flow study using Indium-111 diethylenetriaminepentaacetic acid (111In-DTPA) or low dose (1 mCi) 186RNL following screening and 48-96 hours prior to 186RNL infusion. Failure of the radionuclide to appear in a given CSF compartment is operationally defined as CSF flow block and the patient subsequently classified as a screen fail.

Patients are given supersaturated potassium iodide (SSKI) prior to treatment. 186RNL is delivered intraventricularly through an Ommaya reservoir (5 mL, 1mL/min infusion). Whole Body Planar is completed at end of infusion (EOI) and 3.5-,24-,48-, and 168-hourspost-infusion. SPECT/CT imaging is completed 45-minutes and 24-hours after EOI.

Samples of the CSF are drawn via the Ommaya reservoir at various intervals to monitor radioactivity, estimate absorbed dose, and perform pharmacodynamic studies, such as determination of DNA damage markers, tumor cell count, and standard of care cytology analysis. Urine samples are collected at 0-24-hour and 24-48-hour intervals for radioactivity measurements. Likewise, blood samples are collected after 186RNL infusion at various timepoints to estimate the absorbed dose to red marrow. Study subjects are routinely assessed by MRI (standard of care) until disease progression according to RANO criteria.

PATIENTS

23 patients were treated with 186RNL over 5 cohorts (Cohort 5 is still enrolling to 6 evaluable patients). Patients were treated over three study sites: UT Heath San Antonio (9 patients), UT Southwestern (12 patients), and Northwestern (2 patients). Patients of all primary tumors are included in the Phase 1 study. The majority of the patients had breast cancer (47.8) or lung cancer (26.1%) as their primary tumor.

65.2% of patients were women and 13% were Hispanic. Patients ranged in age (at time of treatment) between 30 and 70 years old at time of consent.

Patients of all primary tumors are included in the Phase 1 study. The majority of the patients had breast cancer as their primary tumor (48%) and lung (26%). Other primary tumors included esophageal (1), melanoma (1), Merkel cell carcinoma (1), pineal parenchymal tumor of intermediate differentiation (1), primary effusion lymphoma (1), squamous cell carcinoma of the neck (1).

TUMOR CELL ENUMERATION

Exploratory endpoints included performing analysis on cerebral spinal fluid (CSF) pre- and post-administration of 186RNL to evaluate pharmacodynamic (PD) markers of 186RNL efficacy. The CNSide assay was used for CSF tumor cell enumeration. CSF was removed via the Ommaya reservoir at various time points and tumor cells were captured using a biotinylated 10-antibody capture cocktail and immobilized in a streptavidin coated microfluidic channel. Cancer cells were identified with various Immunocytochemistry markers (e.g., Cytokeratin, CD45) and cells were quantified via digital analysis of the microfluidic channels. Tumor cells were defined as DAPI positive, CD45 negative, Cytokeratin positive or negative, and Streptavidin positive. Figure 2 provides the percent change of tumor cell counts to predose at 24-hours,48-hours,28-days, and 56-days post infusion for patients with reported data. Table

2 provides average percent change per Cohort (1-3).

	Number of	Dose	Average Percent Change in
Cohort	evaluable	CSF-TC number at Day 28
(mCi)
	subjects	compared to Baseline
1	3	6.6	- 65%
2	3	13.2	- 6%
3	1	26.4	- 81%

Table 2. Average percent change of CSF tumor cells by

Cohort.

Figure 2. Normalized Log (tumor cells) by time for 10 evaluable patients.

IMAGING

Planar and tomographic (SPECT/CT) images were collected from all subjects using a dual-detector SPECT/CT camera. A sealed 186Re radioactivity vial with known 186Re radioactivity (~5% of injected radioactivity) was positioned next to each subject's head and well inside the image field of view at each time of image acquisition for in vivo radioactivity quantification. The planar and tomographic image acquisition uses low energy high resolution parallel-hole collimators (LEHR) with three energy windows setting: 1) Primary energy window: 137 keV (± 10%); 2) Low energy scattering window: 119 keV (± 3.5%); and 3) High energy scattering window: 156 keV (± 3.5%). Representative SPECT/CT images at the two acquisition time points (45- min post EOI and 24-hr post EOI) are shown in Figure 3.

Representative whole body planar imaging in Figure 4 shows durable retention of 186RNL out to 7 days.

45-MIN POST EOI

24-HR POST EOI

Figure 3. SPECT/CT of LM patient in cohort 2 (13.2 mCi injected activity) at 45-min and 24-hours post intraventricular 186RNL infusion through the Ommaya reservoir.

Figure 4. Whole body planar image of LM patient at 0.25-hours,48-hours, and 7-days post intraventricular 186RNL infusion through the Ommaya reservoir.

SAFETY

To date, we have had only 1 DLT and have not reached MTD/MFD. The majority of AEs were mild (Grade 1, 62%) or moderate (Grade 2, 29%). AE grade did not differ by Cohort. Most AEs (59.4%) were unlikely related or unrelated to study drug; only 3 (2.4%) were probably related to study drug. Only 6 SAEs were found, and all were not related or unlikely related to study drug except for one. The one possibly related SAE was also attributed to the patient's pre-existing condition. 42.8% of AEs resolved spontaneously or with treatment.

ABSORBED DOSE

Table 4 reports the average absorbed dose of cranially located, subarachnoid cerebral spinal fluid for the ventricles and cranial subarachnoid (SA) space, ventricles (Lateral, 3rd, and 4th), and cranial subarachnoid space. Additionally, we measured the average absorbed dose in the spinal fluid, liver, and spleen. Organ doses remain low while absorbed dose to the CNS increased with administered dose.

	Ventricles and Cranial	Ventricles (Lateral, 3rd,	Cranial Subarachnoid	Spinal Fluid
Cohort	Subarachnoid Space Absorbed	and 4th) Absorbed	Space Absorbed Dose	Absorbed Dose
	Dose (Gy)	Dose (Gy)	(Gy)	(Gy)
1	24.84	19.26	27.95	6.88
2	40.86	25.43	49.49	20.73
3	63.83	25.96	85.73	44.07
4	164.96	77.07	213.86	77.78
5	207.44	90.11	273.62	142.12

Table 3. Average absorbed doses for patients treated with a single dose of 186RNL. Cohort 5 is still enrolling.

OVERALL SURVIVAL

The median overall survival (OS) for n=10 patients (Cohorts 1-3) was 10 months (95% CI 1-NA) with 5 alive and censored patients at the time of analysis (August 1, 2023) (Figure 3).

Figure 3. Kaplan-Meier analysis for 10 Phase 1 patients.

SUMMARY AND CONCLUSIONS

• 23 patients with LM received a single intraventricular dose of 186RNL between 6.6 and 66.14 mCi through indwelling Ommaya reservoir.
• Only 1 DLT has been observed to date and the MTD/MFD has yet to be reached
• The majority of adverse events were mild or moderate.
• 186RNL circulated throughout the CSF space by 1-hour following administration and persisted in the CSF for up to 7-days.
• Overall organ radiation doses were low.
• CSF tumor cell enumeration decreased up to 91% (max) following 186RNL treatment.
• For patients at time of analysis (10 patients, August 2023), mOS was 10 months.
• A continued dose escalation design to MTD/MFD is open and enrolling.
• Some patients have been treated with multiple doses under investigator INDs.
• Multi-doseand retreatment protocols are in process.

CONTACT INFORMATION: DR. ANDREW J. BRENNER AT [e-mail];

DR. MELISSA MOORE AT [e-mail]	TO LEARN MORE ABOUT RHENIUM (186RE) OBISBEMEDA	DISCLOSURES: THIS STUDY WAS SUPPORTED BY CPRIT DP220039. 186RNL IS AN
CLINICAL TRIAL ID: 153715	AND THE RESPECT-LM CLINICAL TRIAL,
INVESTIGATIONAL PRODUCT UNDER AN APPROVED FDA IND.
CLINICALTRIALS.GOV IDENTIFIER: NCT05034497
VISIT: HTTPS://WWW.RESPECT-TRIALS.COM/LM