Project 3: InHANCE: Fibrosis Imaging Biomarkers of Radiation: An Orphan Drug Study to Evaluate REduction of SeVERity of Symptoms in a Randomized Evaluative Trial (FIBRO2SE-REVERSE)

ABSTRACT: Project 3 Head and neck cancer accounts for approximately 65,000 new cancer cases and results in 13,000 deaths annually in the United States. Recently, the incidence of human papilloma virus (HPV) associated oropharyngeal cancer (OPC) began to increase with more than 30,000 estimated cases annually. Recent efforts to reduce side effects through reduction of therapeutic intensity by either altering concurrent chemotherapy regimens (RTOG 1016) or removing chemotherapy entirely (NRG HN-002) have proven ineffective, such that, for the foreseeable future, radiotherapy with or without concurrent cisplatin will remain a standard of care for non-metastatic disease. Recent data suggest that the majority of survivors may experience moderate-to-severe lymphedema/fibrosis, and almost half of patients may have fibrosis-associated dysphagia. Lymphedema after radiotherapy gradually evolves from a potentially reversible stage to permanent fibrotic changes, and at present, is crudely monitored using time- and expertise-intensive observer-rated physical palpation and endoscopic examination scales. This study aims to address the significant public health burden of radiation lymphedema/fibrosis with a randomized controlled basket “pick-the-winner” study of previously human-piloted FDA-approved orphan drugs using three candidate agents with antifibrotic properties in a Phase II Bayesian trial, while simultaneously embedding imaging biomarker assessment of quantitative MRI relaxometry for muscle fibrosis. Additionally, we plan to develop and validate deep learning-based anatomic imaging measures to quantify and monitor lymphedema/fibrosis clinically using MRI techniques. These strategies, if successful, will define one or more definitive pragmatic drug regimen(s) to mitigate a quality of life altering orphan disease, and address a current unmet need in head and neck cancer survivorship, as it affords potential pharmacotherapeutic reduction in lymphedema/fibrosis using readily accessible agents with integrated therapeutic image-based monitoring that is currently not possible with existing technologies.