Background: rHNSCC commonly affects local or regional sites and is associated with considerable morbidity and mortality. Outcomes of these patients remain poor with limited curative treatment options and low response rates. New modalities that are targeted, minimally invasive, and provide improved tumor response and control while having limited systemic side effects are needed. Photoimmunotherapy (PIT) is a new cancer-targeted platform technology. It is a combination drug and device treatment that utilizes monoclonal antibodies conjugated to a dye (IRDye 700DX) that is photoactivated using nonthermal red light to induce rapid and selective tumor cell death. The objective of this phase 3 study is to evaluate the efficacy and safety of ASP-1929 (EGFR-directed antibody cetuximab-IR700 conjugate) PIT treatment as a monotherapy in patients with locoregional rHNSCC. Methods: A global, multicenter phase 3, randomized, double-arm, open-label, controlled trial of ASP-1929 PIT vs physician’s choice standard of care (SOC) for the treatment of locoregional, rHNSCC in patients who have failed or progressed on or after at least two lines of therapy, of which at least one line must be systemic therapy, is currently underway. Primary endpoints of the study are PFS and OS and the key secondary endpoint is ORR. Key inclusion criteria include: disease not amenable to curative therapy; tumor(s) accessible for PIT light treatment and measurable by CT or MRI; male or female ≥ 18 yrs old with life expectancy > 6 months; ECOG score of 0 to 1. Key exclusion criteria include: history of ≥ Grade 3 cetuximab infusion reaction; distant metastatic disease; tumors invading a major blood vessel unless embolized. The study will include ~275 subjects in a 2:1 randomization (ASP-1929 PIT: Physician’s choice SOC). The physician’s choice SOC arm includes cetuximab, methotrexate, or docetaxel. Tumor(s) are illuminated with 690 nm PIT light treatment 24 hrs following completion of ASP-1929 infusion (640 mg/m²). Clinical trial sites will be in the USA, EU and Asia. Clinical trial information: NCT03769506