Primary liver malignancies have doubled in incidence over the last two decades. These malignancies are now the 4th leading cause of cancer-related mortality worldwide with a 19.6% 5-year relative survival. Hepatocellular carcinoma (HCC) accounts for 90% with cholangiocarcinoma (CCA) accounting for the remainder. Currently, just 20-30% are resectable at presentation with many patients relying on systemic therapy. Beyond resection, effective systemic therapies are lacking, thus new treatment regimens are of significant clinical need. Recent phase III data with combination of Atezolizumab (anti-PD-L1) and Bevacizumab (anti-VEGF) as first-line therapy in unresectable HCC demonstrated improved progression-free and overall survival compared to Sorafenib, thus bringing immunotherapy to the forefront of combating this disease. Despite this improvement, patients experience significantly more adverse events with the addition of anti-VEGF therapy. This combination of Atezolizumab and Bevacizumab is an attractive immunotherapeutic backbone for pairing HCC therapy with means to improve drug delivery and boost response in order to decrease anti-VEGF dosing.~HCC most often develops in the background of chronic inflammation from sustained liver damage, hepatocyte cell death, and compensatory proliferation. During liver injury, hepatic stellate cells (HSCs) transform from quiescent to activated cells, characterized by altered matrix protease activity and deposition of extracellular matrix (ECM) proteins. ECM deposition increases liver stiffness that leads to vascular resistance and hypoxia, stimulating pro-angiogenic factors and subsequent angiogenesis. Secretion of growth factors (TGF-β, PDGF, and FGF-2) by the ECM and tumor cells, attracts fibroblasts from neighboring tissues and aids in transformation to cancer-associated fibroblasts (CAFs).[23] CAFs interplay with the ECM, contributing to further desmoplasia and remodeling through secretion of lysyl oxidases that catalyze collagen cross-linking. The accumulation of collagen cross-links results in marked increase in stromal stiffening and interstitial fluid pressure (IFP) reducing delivery of chemotherapy and immunotherapy Lysyl oxidases (LOX) are a family of 5 secreted copper-dependent amine oxidases (LOX, LOXL1-4) that catalyze the cross-linking of collagen and elastin in the extracellular matrix. High LOX expression has been show to correlate with poor prognosis across a variety of solid malignancies, including hepatocellular carcinoma. This trial pairs PXS-5505 (pan-lysyl oxidase inhibitor) with Atezolizumab and Bevacizumab in patients with unresectable or metastatic HCC. Phase 1b of this study will be an open label safety and tolerability assessment of PXS-5505 (pan-lysyl oxidase inhibitor) with a dose escalation design. The Phase 2 portion of the study will assess the efficacy of combination PXS-5505 with Atezolizumab and Bevacizumab compared to historical standard of care Atezolizumab and Bevacizumab.
This trial will assess the safety and tolerability of PXS-5505 incorporating first-line combination therapy Atezolizumab and Bevacizumab in unresectable or metastatic hepatocellular carcinoma. Phase 2 will assess the efficacy of this combination therapy in unresectable or metastatic hepatocellular carcinoma.