PanDox: Targeted Doxorubicin in Pancreatic Tumours

This study will combine focused ultrasound to generate heat, and a heat-sensitive chemotherapy drug (ThermoDox®), delivered into the blood of participants with non-resectable pancreatic cancer. We will compare this to standard delivery of chemotherapy - the drug Doxorubicin given into the blood without the addition of ultrasound. We aim to determine whether the novel approach to delivering chemotherapy with heating the tumour by focused ultrasound can enhance the amount of drug delivered to pancreatic tumours. This will be measured by analysing a biopsy sample of treated tumour.

PanDox is a phase I prospective, non-randomised, safety cohort study with the primary aim to quantify the enhancement in delivery of intratumoural doxorubicin concentration in pancreatic tumours, for a given systemic dose. Drug release is triggered from systemically circulating ThermoDox® by highly localized hyperthermia induced by extracorporeal ultrasound-guided FUS device at sub-ablative powers. The study will have all patients recruited from a single UK site (Oxford) and will comprise adult patients with non-resectable pancreatic adenocarcinomas. Patients referred to Oncology will have cross-sectional imaging reviewed for suitability of tumour targeting, and MDT (Multi-Disciplinary Team) agreement before being approached. Screening comprises clinical history and examination, routine blood tests, cardiac assessment by ECG (Electrocardiogram) and ECHO (Echocardiogram), abdominal ultrasound examination and a pre-operative assessment to ensure suitability for general anaesthetic. Suitability of potential target lesions will be based on ultrasound examination. The study has an open label design with all participants receiving a single dose of either standard doxorubicin OR systemic ThermoDox® with ultrasound guided FUS targeted at a pancreas tumour using the Model JC200 Focused Ultrasound Tumour Therapeutic System (Haifu Medical, JC200), which is clinically approved (CE-marked) for tumour therapy in Europe and China. Participants who successfully complete screening will be allocated to either Arm A (doxorubicin) or Arm B (ThermoDox® with FUS) based on pre-determined checklist. This is to ensure feasibility and safety of patients to undergo FUS. It also permits patients who have successfully completed screening, but who are not suitable for FUS, to participate in a clinical trial. Baseline imaging is performed in the week prior to intervention and consists of fluorodeoxyglucose (18F-FDG) positron emission tomography / CT (PET-CT) for all patients. Participants in Arm B also undergo dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI). For Arm A patients: following pre-medications, a single intravenous dose of Doxorubicin, 50 mg/ m2 in 250 mL of normal saline or 5% dextrose over a 30-min infusion is delivered as per local practice. For Arm B patients: a single pancreatic tumour (or partial tumour volume), is targeted for drug delivery. Patients will receive pre-medications and general anaesthetic (Fig. 1b), In order to minimise respiratory movement of the target tumour during the intervention, appropriate anaesthetic techniques, such as high-frequency jet ventilation may be employed. High intensity focused ultrasound to cause a small area of tumour ablation will be used to help confirm location targeting accuracy and may give a treatment reference point for Endoscopic Ultrasound Sampling (EUS) biopsy. No more than 2 ablation spots will be applied. Once confirmed, lower-intensity FUS is then moved through the target tumour volume to raise the bulk tumour temperature above the thermal release threshold. This is based on an individualised plan of FUS parameters (power, duty cycle, scanning speed, unit spacing), devised from patient imaging and computer modelling, accounting for differences in propagation path length and overlying tissue structures. (Gray et al., 2019) At target temperature, a single intravenous dose of ThermoDox®, 50 mg/ m2 in 250 mL of normal saline or 5% dextrose over a 30-min infusion is delivered concurrently to FUS, in line with the pharmacy manual provided by the manufacturer. FUS will continue following infusion, for no longer than two hours from infusion commencing. FUS-mediated hyperthermia is delivered under ultrasound guidance using clinically approved treatment modes of the therapeutic device, namely either linear (moving beam) or dot (shot-by-shot) mode, using the on-board plane-by-plane treatment planning tool to encompass all or part of the target tumour volume. Device settings are chosen to achieve hyperthermia in the range of 40-42 °C in the target region. The specific treatment parameters will naturally vary depending on tumour anatomy The addition of a passive material layer for beam expansion may be used to expand the beam size for optimal heating control and efficiency. Supplemental hand-held diagnostic ultrasound probes may be used during treatment to monitor and quantify natural target motion and/or the presence of cavitation. For all patients, tumour sampling for primary end point will be acquired via EUS, performed within thirty hours of treatment. These will be analysed using a Good Laboratory Practice-validated high performance liquid chromatography (HPLC) assay, to quantify doxorubicin at the targeted site. Plasma samples are collected immediately before the start of ThermoDox® infusion, immediately after completion of ThermoDox® infusion, and immediately after completion of FUS exposure, to evaluate doxorubicin pharmacokinetics. In the post-treatment period, Arm B patients will have a repeat DCE-MRI scan for comparison with baseline. Additionally, all study patients will have follow-up imaging performed at 21days following intervention to assess potential response in the target tumour activity and volume.

• Pancreatic Ductal Adenocarcinoma
• Pancreatic Cancer Stage IV
• Pancreatic Cancer Non-resectable
• Pancreatic Cancer Metastatic

• DEVICE: Focused Ultrasound
• DRUG: Doxorubicin
• DRUG: ThermoDox

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