Introduction: MDNA55 is a targeted immunotherapeutic agent comprising a circularly permuted interleukin-4 (cpIL-4) fused to a truncated version of Pseudomonas exotoxin A (PE). MDNA55 binds to the interleukin-4 receptor (IL-4R), over-expressed by GBM cells and immunosuppressive cells of the tumor microenvironment (TME), and is endocytosed with the cleaved PE domain inducing tumor cell death via ADP-ribosylation of the Elongation Factor-2.
Methods: MDNA55-05 is a multi-center, single-arm, Phase 2b study of intratumoral infusion of MDNA55 in rGBM using a stepped catheter, infusion modelling (for catheter placement) and intra-operative real-time imaging of drug distribution. Infusions are started at 3µL/min/catheter then progressively increased under real-time MRI imaging according to the observed pattern of drug distribution and proximity of key structures.
An interim evaluation of CED success, tolerability and safety was completed.
Results: 10 rGBM subjects at 1st or 2nd recurrence with tumors 1.8 – 4.3 cm in diameter received 12-66ml of MDNA55 delivered at a concentration of 1.5 µg/mL via 1-3 catheters at flow-rates of up to 15µL/min/catheter.
No SUSARs have been reported and no reports suggestive of acutely raised ICP, cerebral irritation or volume-related effects. AEs are generally consistent with the underlying disease.
Some remarkable distributions have been observed. Tumor coverage ranged from 43% to 100%, with 70% and 40% coverage of 1cm and 2cm penumbra respectively. Ratio of volume of distribution (Vd) to the volume infusion (Vi) ranged from 2.2 to 0.6. Reasons for lower Vd/Vi ratios will be detailed.
When catheter placement was inaccurate, realtime imaging of GdDTPA distribution enabled adjustments to catheter depth which dramatically improved tumor coverage.
Conclusions: Step-up of infusion rates under real-time MRI guidance enables delivery of MDNA55 by CED in rGBM at infusion rates of up to 15µL/min/catheter. MRI guidance is therefore critical for optimal drug distribution in brain tumors. Reassuring initial safety review enabled ongoing recruitment in the study.
Patient Care: describes state-of-the-art learnings for the optimzation of CED technique to enhance safety and drug distribution in rGBM.
Learning Objectives: By the conclusion of this session, participants should be able to
1) Understand how to optimise intratumoral drug delivery by CED
2) Describe what can be achieved in terms of volumes and infusion rates
3) Learn how case planning and catheter placement can be optimized by pre- and peri-operative imaging
4) Understand the impact of enhanced surgical techniques on drug distribution
5) Recognise the emergent safety profile of MDNA55 administered by CED in rGBM