Background: Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). Broad access to CTs in this population is challenging due to an increased prevalence of comorbidities and ageing-related conditions. However, as population-age increases, more and more elderly patients are diagnosed with LA-HNSCC although many are not eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). CRT-related toxicities, treatment burden and compliance are a concern. NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of radiotherapy without additional toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, the combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study was initiated and is now recruiting. Methods: NANORAY-312 [NCT04892173] is a global, open-label, randomized (1:1), 2-arm, Investigator's choice Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be known. In addition to the primary tumor, a single accessible LN in the neck is eligible for intranodal injection. The primary objective is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability and quality of life. Enrollment began in January 2022 and is ongoing. Clinical trial information: NCT04892173.