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Early-Phase Interventional Trials in Oral Cancer Prevention.

ABSTRACT: 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.

SUBMITTER: McCarthy C

PROVIDER: S-EPMC8345124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:TARGET (Tumour characterisation to Guide Experimental Targeted therapy) seeks to optimise the pathway for molecular characterisation of all patients entering early phase cancer trials to inform clinical decision-making on optimal therapy. Performance status (PS) was developed to assess a patient’s ability to perform a variety of activities to further inform clinical decision making on optimal therapy including appropriate inclusion in clinical trials. However, the quality of present algorithms to assess performance status are limited and based on a semi-quantitative clinician assessment. In particular, a common eligibility criterion for entry into early phase cancer clinical trials is a life expectancy of >3 or 6 months. Here we investigate proteomics as a means of more objective and quantitative assessment of both performance status and thus likely prognosis prior to clinical trial enrolment. Improved patient stratification at enrolment would reduce the number of patients unnecessarily exposed to potentially toxic drugs and decrease withdrawal from trials. Plasma samples from patients enrolled into the TARGET trial were analysed using the mass spectrometry (MS) technique: Sequential window acquisition of all theoretical fragment ion spectra (SWATH) MS. SWATH-MS was used on a discovery cohort of 73 patients to identify proteins that could differentiate patients into either a good or poor prognosis. A three-protein panel showed a stronger prediction of overall survival (p = 0.000086) compared to PS (p = 0.001). This panel was then tested against a validation cohort of 77 patients. The panel was determined as being a significant (p = 0.000451) predictor of overall survival whereas PS was not significant. The panel had a receiver operating characteristic curve area under the curve (AUC) of 0.73 in the validation set; the AUC of PS was 0.54. This signature can now be developed further in larger patient populations to assess its utility in a clinical setting.

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Early-Phase Interventional Trials in Oral Cancer Prevention.

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