PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) of hafnium oxide nanoparticles NBTXR3 (NBTXR3) activated by radiation therapy (RT) (hereafter referred to R3/RT).

SECONDARY OBJECTIVES:

I. To evaluate the anti-tumor response of R3/RT. II. To evaluate the safety and feasibility of R3/RT. III. To evaluate time-to-event outcomes.

EXPLORATORY OBJECTIVES:

I. To evaluate the body kinetic profile of intratumorally injected NBTXR3. II. To evaluate time to event outcomes for subjects with clinical staging of locally advanced, unresectable disease.

III. To evaluate resectability conversion rates. IV. To evaluate surgical outcomes in subjects who undergo surgery after radiation therapy.

V. To associate radiomic measurements with outcomes. VI. To evaluate biomarkers of response in subjects treated with R3/RT.

OUTLINE: This is a dose-escalation study of NBTXR3.

Patients receive NBTXR3 intratumorally (IT) on day 1. Patients then undergo 15 fractions of intensity modulated radiation therapy (IMRT) between days 15-43 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month and then every 3 months for up to 1 year.