Report of Phase 1 Part A of the ReSPECT-LM Trial: Rhenium (186Re) Obisbemeda (186RNL) in Leptomeningeal Metastases (LM)
Introduction
Leptomeningeal metastases (LM) is a devastating clinical complication that occurs when cancer cells invade the leptomeninges and cerebrospinal fluid (CSF) of patients with malignant tumors; it is diagnosed in approximately 5% of patients with metastatic cancer. Typical treatment strategies include systemic therapy for the primary disease, as well as neuroaxis-directed therapy, which may include intrathecal chemotherapy or radiotherapy. 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. Rhenium (186Re) obisbemeda (186RNL), a next generation radiotherapeutic, is BMEDA-chelated 186Re encapsulated in liposomal nanoparticles. 186Re has a 90-hour half-life, ~2 mm tissue path length, and 137 keV γ-decay that allows real-time imaging of in vivo drug distribution by SPECT/CT. 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. 186RNL is infused via Ommaya reservoir (intraventricular catheter).
Methods
ReSPECT-LM is a multi-center, open-label, sequential cohort 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 LM patients. The primary objective of the Phase 1, Part A was to determine an MTD/MFD over 3 cohorts utilizing a modified 3+3 Fibonacci design. Dose level 1 (6.6 mCi) was based on preclinical studies, with dose doubling for cohorts 2 and 3. Patients included on study were at least 18 years of age, had proven and documented LM (EANO-ESMO Clinical Practice Guidelines Type 1 and 2, except for 2D) from any primary cancer, Karnofsky performance status of 60-100, and standard organ function requirements. 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 illness restrictions were excluded. A diagnostic CSF flow study using 111In-DTPA was performed prior to 186RNL infusion to check for flow blocks. 186RNL was delivered intraventricularly through an Ommaya reservoir. Whole Body Planar and SPECT/CT imaging was completed at various intervals for in vivo radioactivity quantification. Samples of the CSF, blood, and urine were analyzed at various intervals to monitor radioactivity, estimate absorbed dose, and perform pharmacodynamic studies.
Results
Ten of 13 patients with LM successfully received a single intraventricular dose of 186RNL between 6.6 and 26.4 mCi through Ommaya reservoir; one patient received a second dose under compassionate use. No DLTs were observed, the MTD/MFD was not reached, and most AEs were Grade 1 and 2. 186RNL circulated throughout the CSF space by 1-hr following administration and persisted in the CSF for up to 7-d. CNS structures showed a linear increase of absorbed dose with increasing administered dose. Organ radiation doses were low, with the liver, spleen, and bladder wall having the most prominent 186RNL clearance but significantly below any absorbed dose concerns for a critical organ. CSF tumor cell counts decreased up to 91% following treatment. 6/10 patients remain alive with a median OS of 10 months (95% lower confidence interval of 1 month).
Conclusion
186RNL is a novel radiotherapeutic that has been shown to be safe and well tolerated in 10 patients with LM, up to 26.4 mCi. In addition to reductions in tumor cell count, patients reported an improvement in quality of life and had a median OS of 10 months. A continued dose escalation to MTD/MFD (Phase 1, Part B; Cohorts 4-7) is open and multi-dose and retreatment protocols are being explored.