CUBIC - A Phase I/II study of the CXCR2 inhibitor, AZD5069, in combination with Durvalumab (MEDI4736), in patients with advanced Hepatocellular Carcinoma (HCC)
HCC is one of the most common cancers worldwide and the third commonest cause of cancer deaths. HCC complicates chronic liver disease, the incidence of which is increasing dramatically in the UK, attributed to viral hepatitis, alcohol excess, obesity and type II diabetes - related liver disease. Most patients will present with inoperable disease and will ultimately develop disease that is not accessible to loco-regional therapies, and who will then be candidates for systemic anti-cancer therapy.
Tyrosine kinase inhibitors have modest benefits as either first- or second-line therapy in advanced HCC. Inhibition of the immune checkpoint interaction between PD-1 and PD-L1 has promising activity in patients with advanced HCC, but does not improve overall survival as monotherapy. More recently, the combination of bevacizumab and atezolizumab has demonstrated an improved progression-free and overall survival. Nevertheless, survival remains disappointing and novel therapies are needed for this unmet medical need.
Pre-clinical studies in Glasgow and Newcastle suggest that inhibiting neutrophil accumulation in chronic liver disease or targeting their tumour-promoting activities may offer therapeutic opportunities. The primary immune function of CXCR2, the receptor for a number of human chemokines, is the regulation of neutrophil migration and it also regulates the migration of myeloid—derived suppressor cells (MDSCs). In pre-clinical studies, CXCR2 inhibition reduces liver tumour burden and tumour score in vivo and synergises with anti-PD-1 inhibition to prolong survival.
We hypothesise that AZD5069, by inhibiting CXCR2 and, therefore, depleting MDSCs and neutrophils in the liver tumour microenvironment, can enhance the anti-tumour efficacy of PD-L1 pathway antibodies, leading to improved overall survival. Based on these studies we are initiating CUBIC, a multi-centre, open-label, phase I/II study funded by CR-UK, to determine the recommended phase II dose of AZD5069 in combination with Durvalumab in patients with advanced HCC and to determine the anti-tumour efficacy of this combination in patients with advanced disease.
The dose escalation part will use a keyboard design with a target (dose-limiting) toxicity rate of 30% and an acceptable toxicity range of 25 – 35%. After the recommended phase II dose has been identified, an additional cohort of patients will be recruited to determine the anti-tumour efficacy of this combination in patients with advanced HCC using a Simon’s two-stage design.
Exploratory endpoints: pharmacodynamic studies in blood, pre- and on-treatment biopsies of tumour and of non-malignant liver, and will include biomarkers of CXCR2 Inhibition and proof of mechanism biomarkers. Predictive biomarker studies (blood, tumour) include biomarkers of the CXCR2/PD(L)1/immune axis, CXCR2-regulated signal transduction pathways in HCC, biomarkers of proliferation, and tumour mutational status to predict for response and provide insight into the potential mechanisms involved in immune responsiveness or evasion.
This study exemplifies our approach to discover and develop new therapeutics by manipulating the immune system to treat cancer, including by combining immunotherapies with other targeted therapies. The study is scientifically driven, arising from our own laboratory programmes and those of our collaborators, and developed in partnership with pharmaceutical industry collaborators. The study is coordinated by the CR-UK Glasgow Clinical Trials Unit and will recruit patients from 9 ECMCs in the UK. We will maximise the value of the biological and clinical data in tumour and liquid biomarker studies in collaborating laboratories across 5 institutions including the Glasgow Translational Pharmacology Laboratory (ECMC funded) and in the Glasgow Precision Oncology Lab