Phase I trial of acoustic cluster therapy (ACT) with chemotherapy in patients with liver metastases of gastrointestinal origin (ACTIVATE study).

Abstract

TPS3145 Background: Response to existing chemotherapeutics (chemo) can be limited by exposure, itself limited by systemic toxicity. Interstitial fluid pressure can impede transport of drugs with, in some cases, <5% of systemic chemo penetrating the target tumour. ACT is an innovative platform technology using sonopermeation to induce ultrasound (US) mediated targeting of therapeutic agent of choice by co-administration of an emulsion of microbubble-microdroplet clusters (PS101) for intravenous injection. Dual-frequency US is applied to tumor tissue to concentrate the drug through expansion and oscillation of the clusters, increasing tumoral penetration. Early pre-clinical models of ACT indicate significant increase in uptake of co-administered product at the US targeted site and have demonstrated enhanced efficacy outcomes with co-administered ACT across a range of cancer models. All studies showed significant benefit in disease response and tumour regression/inhibition versus drug alone. The combination of US, microbubbles and chemo has been shown to be feasible in a clinical setting using commercially available equipment with no additional toxicities. This first in human study will primarily investigate the safety and tolerability of PS101 in combination with chemo together with any differential response in ACT-treated versus control lesions to identify the phase 2 recommended dose. Methods: This is an open label non-randomised study with central blinded assessment of tumor response. The study comprises two parts: Part 1, a dose escalation in a 3+3 design followed by dose expansion in Part 2. Patients with advanced solid tumors with liver metastases for whom FOLFOX/FOLFIRI is considered an appropriate treatment option are eligible for Part 1 (n=6-12); two separate cohorts of patients with liver metastases, one with metastatic colorectal cancer eligible for 1L or 2L standard of care (SOC) FOLFOX/FOLFIRI (n=25) and one with metastatic pancreatic ductal adenocarcinoma (n= 6) eligible for SOC gemcitabine-nab-paclitaxel will be treated in Part 2. The starting dose of PS101 is 20 µL/kg with a maximum feasible dose of 40 µL/kg. In Part 1, after sentinel administration of PS101 for PK profiling and toxicity assessment, patients receive PS101 (given as i.v. bolus x 3) in combination with FOLFOX or FOLFIRI and US (to one target lesion) in four q2w cycles. The DLT evaluation period comprises the PK-assessment period plus two cycles of ACT plus chemo. Patients receive a further two cycles of ACT and chemo prior to evaluation of tumor lesions by CT/MRI at the Week 8 timepoint. Assessment is made of the target lesion and the pre-defined control lesions outside of the US field. Part 1 has enrolled 5 patients without DLT, with part 2 expected to start in mid-2021. Clinical trial information: NCT04021277.