Background: PEP503 (aka NBTXR3), a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is designed for intratumoral injection to increase radiation energy deposition within solid tumors and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. PEP503 nanoparticles plus RT has been tested in elderly HNSCC patients and has demonstrated a good safety profile. The phase 1b part of the study aimed to test the feasibility and the recommended phase 2 dose (RP2D) of PEP503 intratumoral injection when added with low-dose (LD) weekly cisplatin-containing chemoradiation (CCRT) in HNSCC. Methods: Patients who had T3-4 locally advanced HNSCC suitable for CCRT were eligible. An intratumoral single injection of PEP503 was performed 24 to 72 hours before the start of CCRT: consisting of IMRT (70̃72 Gy, 2-2.12 Gy/fraction) and weekly cisplatin (low dose, 40 mg/m²) concurrently during IMRT. Traditional 3+3 design was planned for dose escalation and 5 levels of PEP503 were planned, including 5%, 10%, 15%, 22%, and 33% of the baseline GTV by MRI. PEP503 Intra-tumor dispersion was anayzed by CT-scan. Results: Twelve (12) patients (male/female: 11/1; oral cavity/oropharynx: 11/1) were enrolled, with 3, 6, and 3 patients at 5%, 10%, and 15% PEP503 dose levels, respectively, in combination with LD cisplatin CCRT. DLTs were observed in one patient at 10% dose level which were G3 ALT and G3 AST increased. Common G3 AEs observed across dose levels were stomatitis (50.0%), WBC decreased (33.3%), decreased appetite (16.7%), neutrophil count decreased (16.7%), and leukopenia (16.7%), and only one G4 AE (hyponatraemia) was observed. CT images demonstrated PEP503 within the tumor contour after injection throughout the CCRT period. Hafnium, for all patients, was either not detected or below the Lower Limit of Quantification (LLOQ) in the circulation 60 minutes after PEP503 intratumoral injection, and not found in urine. DCR was achieved in 100% of patients with responding patients for an ORR of 58.3%. No subjects received salvage surgery after study treatment. Study was terminated early before MTD and RP2D could be determined. Conclusions: Adding PEP503, a radioenhancer, via a single intratumoral injection to weekly cisplatin-containing CCRT was feasible and safe for patients with locally advanced or recurrent LA-HNSCC. RP2D was not reached due to study early termination. Clinical trial information: NCT02901483.