“CEeDD: “A First-in-Human Clinical Investigation of Cavitation-Enhanced Drug Delivery to Solid Tumours by co-Administration of Sonosensitive Particles and Application of Extracorporeal Ultrasound in Patients with Colorectal Metastases to the Liver”

Question: Can a low-intensity, mobile ultrasound system used in conjunction with systemically administered tumour-penetrating cavitation nucleation agents be used safely to enhance the delivery, distribution and therapeutic efficacy of unmodified therapeutic antibodies?

Background: In mCRC, neo-adjuvant therapy has become standard-of-care to reduce liver metastases and potentially enable curative surgery.

Half of mCRC patients receive neo-adjuvant antibody-treatment (Cetuxumab) and adjuvant chemotherapy (FOLFIRI) with a response rate of ~58% and median survival of 23.5 months. There is a significant improvement in overall survival for responders who proceed to resection.

Cextuximab, like all antibodies, is limited by poor delivery and penetration into solid tumours, with ~0.01% of the systemically-administered dose per tumour gram found 24h after infusion, regardless of indication.

In response, OxSonics Therapeutics has developed SonoTran, comprising injectable SonoTran Particles (SPs) and an ultrasound SonoTran System (SS).

Upon exposure to ultrasound using SS, air bubbles on the SPs cause local micro-pumping, propelling the antibody through the leaky vasculature into solid tumours.

Pre-clinical evidence suggests this micro-pumping enhances antibody dose, delivery, and volumetric distribution in treated tumours.

Aims/Objectives: This research seeks to validate a) the safety of SonoTran intervention without drug b) performance of the SonoTran intervention in the presence of Cetuximab prior to surgery c) safety and radiological efficacy of SonoTran intervention on every treatment cycle with Cetuximab+FOLFIRI.

Methods: Proposed clinical study comprising: a) n=9 patients (SonoTran only) to demonstrate treatment safety b) n=12 surgery-eligible patients (n=6, Cetuximab+resection; n=6, Cetuximab+SonoTran intervention+resection) to quantify delivery/distribution in resected tissue. c) n=24 neo-adjuvant patients (n=12,Cetuximab+FOLFIRI, n=12,Cetuximab+FOLFIRI+SonoTran intervention) comparing PET-CT/CT/MR response of the SonoTran-treatment to control.

Timelines: 15/12/2020:Ethics/MHRA submission 01/03/2021:Approval; trial opens 30/09/2023:Full study results reporting Impact/Dissemination: Trial data will support future, powered trial applications for CE-marking and FDA approval, and future NICE guidance. Publications will advance the field of therapeutic ultrasound and clinical practice.