Early-Phase Interventional Trials in Oral Cancer Prevention

Simple Summary Oral cancer is a devastating disease with increasing incidence worldwide. Oral epithelial dysplasia (OED) is a potentially malignant disorder and patients with OED are at increased risk of developing oral cancer. Current strategies for management of OED include surgery or close observation and both fail to address the underlying pathogenesis of the disease. There is an urgent need for evidence-based medical treatments for OED to prevent oral cancer development in this cohort. Chemoprevention trials to date have not delivered therapeutic agents for routine clinical practice. Historically, there has been significant heterogeneity in the design of oral cancer chemoprevention trials, with most failing to selectively recruit patients with biopsy-proven OED, which limits the usefulness of the findings in the OED population. The present paper aims to review the current evidence and the methodology of early-phase trials in oral cancer chemoprevention. Novel strategies in oral cancer chemoprevention will also be discussed. The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.