First-in-human study of cavitation-enhanced drug delivery (CEeDD) by sonosensitive particles and focused ultrasound applied to colorectal metastases in the liver.

3549 Background: Effective treatment of colorectal liver metastases is limited by poor drug delivery, particularly for monoclonal antibodies, the large molecular weight of which, together with abnormal tumor vasculature, elevated interstitial pressure and dense stromal architecture, restricts penetration and distribution into solid tumors. This first-in-human study evaluated a novel platform combining intravenously infused sub-micron gas-stabilizing sonosensitive particles with novel handheld ultrasound probe to cause cavitation that enhances the transport of systemically co-administered therapeutics (i.e. cetuximab/irinotecan) from the vasculature into tumors, without the need to modify these therapeutics. Methods: The study comprised 3 patient cohorts. Cohort 1 evaluated the safety of ultrasound activation of intravenously infused sonosensitive particles alone, without drug. With safety confirmed, Cohort 2 assessed intratumoural drug concentration in patients undergoing surgical resection after receiving subtherapeutic irinotecan and cetuximab, with or without ultrasound-activated particles. Cohort 3 evaluated early efficacy in patients receiving standard of care FOLFIRI and cetuximab, with or without cavitation in repeated treatment cycles. Primary endpoints were grade 3 or higher adverse events in Cohort 1, intratumoural drug concentrations in Cohort 2, and radiological tumor response in Cohort 3. Results: In Cohort 2, seven evaluable patients underwent resection, with 4 in the control arm and 3 in the ultrasound-mediated-cavitation arm. Mean cetuximab concentrations were modestly higher in the tumour centre (3.6 vs 3.2 ng/mL) and mid radius (4.1 vs 3.7 ng/mL), and substantially higher at the tumour periphery (7.1 vs 3.7 ng/mL) in the ultrasound-mediated-cavitation arm, while liver margin levels were comparable. There was no appreciable beneficial difference in the mean tumour concentrations of irinotecan and its metabolites between the two arms. In Cohort 3, 10 evaluable participants completed at least 3 treatment cycles (control n=3; cavitation n=7). Objective response rate was 66.7% in the control arm versus 85.7 % with cavitation. Conclusions: Cavitation with sonosensitive particle infusion demonstrated a favourable safety profile, increased intratumoural antibody delivery, and showed early signals of enhanced anti-tumour activity, supporting further clinical development. Clinical trial information: ISRCTN17598292. Cohort Number treated Primary endpoint Key findings 1 9 Safety No grade 3 or higher events; sustained cavitation in the target region. 2 7 Drug levels Increased cetuximab concentrations in the tumours treated with cavitation (7.1 vs 3.7 ng/mL) 3 10 Radiological response Enhanced radiological response (ORR of 85.7% in patients treated with cavitation) ORR = objective response rate based on FDG PET-CT.