Title: “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”
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Antibodies (AB) are one of the most effective drug groups to fight cancer, as they accurately target cancer cells more than normal cells and can even sometimes train the patient s own immune system to fight the cancer. However, antibodies are big molecules, more than 10x bigger than standard cancer drugs, and therefore it is more difficult for them to move out of blood vessels into the tumour, and so they cannot be as effective as they should be. Our group (involving the University of Oxford, the NHS and OxSonics Therapeutics) will test the combination of an anticancer antibody, given at the same time as tiny gas bubbles, which are then vibrated with ultrasound (US) waves as they pass through the tumour. In the lab we have shown that the gas bubbles, as they pulsate under the US, act like pumps, pushing the AB deep in to the tumour; allowing 4 x the amount of AB into 3 x the number of cancer cells, so more than an order of magnitude greater drug delivery to the tumour. This present project will look mainly at the safety but also at the effectiveness (in terms of AB delivery) of this combination. Initially 9 colorectal cancer patients with liver metastases (CRLM) will be treated with US and gas bubbles alone, to ensure that this is safe and tolerable in this group of patients. Then we will look at two groups of CRLM patients alongside each other. One group will be patients who would normally be going straight for liver surgery to remove their tumours. They will be given a single dose of cetuximab AB (a standard treatment for CRLM) and half of these patients will also receive the gas bubble / US intervention, the other half will not. All will have their secondary tumours examined under the microscope and with special stains to see how far the AB got into the tumour. The second group will be patients who are not felt to be candidates for immediate removal of their CRLMs. All of these will receive the standard of care treatment of chemotherapy and cetuximab AB, and half of them will also receive the gas bubble/US intervention. We will compare their responses and see how many of them become candidates for CRLM surgery. This is important as removal of CRLMs gives the best chance of longterm control / cure. Analysing the outcomes from all these patient groups will give us important evidence about the safety of this novel intervention, and further give us preliminary data about its ability to improve AB delivery and enhance effectiveness, improving outcomes for patients with CRLMs.

Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS