Tolinapant and Radiation for Cisplatin-Ineligible, Previously Untreated, Locally Advanced Head and Neck Cancer

Primary Objective: To evaluate the safety and tolerability of the recommended phase 2 dose (RP2D) of tolinapant when given in combination with radiation. Secondary Objectives: To assess preliminary efficacy of the combination of tolinapant and radiation in cisplatin ineligible patients with head and neck cancer as determined by locoregional control, two year progression-free survival (PFS), and two-year overall survival (OS). Exploratory Objective: To compare immune cell infiltrates following the first cycle of tolinapant + radiation, compared with baseline biopsy tissue and peripheral blood. TERTIARY/EXPLORATORY OBJECTIVES: I. To assess the effects of the combination of tolinapant + radiation on immune cells in blood and tumor. II. To assess the association between immune responses and FADD expression in tumors. OUTLINE: Patients undergo standard of care radiation therapy for a total of 35 fractions over 6-7 weeks and receive tolinapant orally (PO) daily for 7 days during weeks 1, 3, 5, and 7 of radiation therapy in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up 1, 3, 6, 12, and 24 months.