Background
Pancreatic cancer is the fourth most common cause of cancer related death in Australia with a five-year survival rate of only 3.2% for metastatic disease at diagnosis. The current treatment landscape for advanced pancreatic cancer is limited to systemic chemotherapy. The unique desmoplastic stroma and immunologically “cold” tumour microenvironment (TME) contributes to primary treatment resistance. Immune checkpoint inhibitors have revolutionised management of many solid organ malignancies but has not yet shown utility in pancreatic cancer.
Here we present a clinical trial design to investigate the efficacy of repurposed itraconazole (antifungal agent) in combination with immunotherapy as treatment for advanced pancreatic adenocarcinoma (PDAC).
Methods and Results
Preclinical models in the Pajic lab demonstrates that itraconazole modulates the TME with reduced collagen deposition and vascularisation, reduces metastatic spread, and increases survival in combination with chemotherapy. Itraconazole also alters the immunosuppressive TME by reducing cancer associated fibroblast (CAF) population, polarising tumour associated macrophages (TAMs) towards anti-tumour M1 phenotype, increasing CD8+ T cell activation while concurrently reducing CD4+ T cells and FoxP3+ T regulatory cells. Notably, itraconazole also improves the outcomes of immunotherapy.
Based on these results we have designed a clinical trial which has received HREC approval to assess the safety and preliminary efficacy of SUBA-itraconazole (more bioavailable itraconazole formulation) and cadonilimab (bispecific antibody targeting PD-1 and CTLA-4) as maintenance treatment in advanced pancreatic cancer.
This Phase I/II study will enrol patients who have received at least 16 weeks of first line chemotherapy for advanced pancreatic cancer without evidence of progressive disease. We have implemented a BOIN design with initial dose escalation phase with three potential cohorts to determine the recommended phase 2 dose of SUBA-itraconazole in combination with cadonilimab given at a weight-based dose. Blood and tumour tissue will be collected to investigate the pharmacokinetics of study drug treatments, identify potential biomarkers and explore changes in immune cell populations.
Conclusion
Based on preclinical evidence demonstrating that itraconazole can modulate PDAC TME and improve immunotherapy responses; our clinical trial design will investigate the safety and preliminary efficacy of SUBA-itraconazole and immunotherapy as maintenance treatment in advanced pancreatic cancer.