Rhenium-186-NanoLiposome (186RNL) in the treatment of relapse/recurrent glioblastoma (rGBM): A novel approach for cancer therapy

Introduction: Purpose: Update on the current Phase 1/2a clinical trial of ¹⁸⁶RNL administered by convection enhanced delivery (CED) to treat recurrent glioblastoma and other cancers.

Background: Rhenium-186 (¹⁸⁶Re) (T½ 89.2 hours) with 10% 137 KeV γ-ray has pharmacokinetics similar to radioiodine and is in the same Periodic Table column as Technetium. Liposomes of ~100 nm diameter can be radiolabeled with ¹⁸⁶Re using a previously described BMEDA method with > 80% labeling efficiency of the radiolabeled ¹⁸⁶RNL. ¹⁸⁶RNL enables localized cancer therapy via direct image-guided needle insertion with convective spread within the tumor and sustained retention in the tumor post-delivery.  Uptake in the thyroid, salivary gland and stomach of metabolized ¹⁸⁶Re, chemically analogous to free ^99mTc, can be efficiently blocked by oral potassium iodine [KI] saturation thereby accelerating its rapid renal urinary ¹⁸⁶Re clearance.  This novel localized radio-nanotherapeutic approach has enormous potential in a large variety of tumors as either ¹⁸⁶RNL or generator obtained ¹⁸⁸RNL where local tumor control is difficult or all other therapies exhausted, ineffective or toxic.  Repeat RNL therapy is possible as the ¹⁸⁶RNL radiation dose is delivered directly, locally and safely.

Methods: A dose escalation study for treatment of recurrent glioblastoma has been performed through 7 cohorts with radioactivity and volumes of ¹⁸⁶RNL gradually increasing from 1 mCi in Cohort 1 to 22.3 mCi in the 7^th cohort at a concentration of 1.5 mCi/ml to 2.54 mCi/ml delivered intratumorally by convection enhanced delivery (CED).  BrainLab iPlan Flow Software and a Varioguide system were used for treatment planning and catheter placement.^  To improve the tumor volume coverage in escalating cohorts, the catheters were increased from 1 to 3-4 catheters starting from cohort #4.  During cohort progression the rate of administration increased from 5 ml/min to 20 ml/min. 

Results: SPECT/CT images fused to MRI and whole-body imaging, revealed sustained locoregional retention and distribution in the glioblastoma&nbsp;tumor over 8 days. The mean administered&nbsp;¹⁸⁶RNL locoregional retention in the tumor region at the end of infusion was 85.9% ± 17.1% ID (n = 18) and at 8 days post-infusion was 46.6% ± 16.7% ID (n = 17).&nbsp;&nbsp;Up to four catheters effectively enhanced locoregional drug distribution and tumor volume coverage. This increased rate of RNL administration and the use of multiple catheters decreased the average treatment time from > 8 hours to ~ 3 hours with &nbsp;¹⁸⁶RNL treated volume increasing to 54.2 ± 22.9 ml (n = 6) in cohorts 6 and 7).&nbsp;&nbsp;The cleared&nbsp;¹⁸⁶RNL was metabolized and rapidly excreted from the body via the kidneys like ¹³¹I&nbsp;with&nbsp;¹⁸⁶Re excretion being enhanced when saturating KI doses were pre-administered.&nbsp;&nbsp;Following 5^th-7^th&nbsp;cohorts dose escalation, the mean radiation absorbed dose delivered directly to the tumor volume increased to 354.7 ± 144.0 Gy, while whole brain was 1.32 ± 1.06 Gy, and whole body was 0.16 ± 0.04 Gy (n = 6). Initial treatment results are very encouraging with a 13-patient subset receiving a radiation dose >100 Gy with an average 487 day survival with 6 of 13 patients in this subset still alive. In contrast, in 9 patients receiving radiation doses of <100 Gy, average survival was 167 days with no patients remaining alive. Importantly, no clinically meaningful SAEs, AEs, or tolerability observations have been reported.

Conclusions: &nbsp;¹⁸⁶RNL provides local, direct therapy with high radiation absorbed doses for local tumor control with minimal brain and whole-body radiation exposure. In this preliminary Phase I/2a data, beneficial effects were observed when doses > than 100 Gy dose are delivered to >80% of a tumor without dose-limiting toxicity. Future studies are planned with&nbsp;¹⁸⁶RNL including leptomeningeal metastasis treatment (NCT05034497&nbsp;at&nbsp;clinicaltrials.gov).&nbsp;¹⁸⁶RNL therapy is in late-stage planning for the treatment of childhood glioma.&nbsp;&nbsp;

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