First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas

Abstract

This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS). Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion. Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible. A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. .

Nanoparticles in the clinic: An update

“…NBTXR3/Hensify is a 50 nm crystalline hafnium oxide nanoparticle with negatively charged phosphate coating, developed and marketed by Nanobiotix . NBTXR3/Hensify enhances external radiotherapy via a physical mode of action that relies on hafnium's natural radioenhancing properties . Specifically, the interaction between ionizing radiation and hafnium facilitates a higher energy deposit as compared to ionizing radiation without hafnium interaction; this results in the generation of significantly more electrons and increases radiation‐mediated cell death from standard radiation oncology procedures .…”

Rethinking cancer nanotheranostics

“…In another study, it was shown that NBTXR3, a 50 nm hafnium oxide nanosphere, can substantially enhance radiation therapy efficacy when intratumourally injected into different tumour xenograft models 76 . This nanoparticle formula is in phase II/III clinical trials for improving radiation therapy against advanced soft tissue sarcoma of the extremities 77 , and in phase I/II for head and neck cancer, liver cancers (both hepatocellular carcinoma and liver metastases), prostate cancer and rectal cancer radiation therapy. Recently, AGuIX, a ~3 nm polysiloxane and a Gd-DTPA conjugate, was investigated as a nanoparticle radiosensitizer 14 .…”

Emerging Strategies of Nanomaterial‐Mediated Tumor Radiosensitization

“…More importantly, Hf is a high Z atom ( Z = 72), which enables it to be used as radiosensitive agent . HfO 2 nanoparticles can serve as a radiosensitizer by physical mechanism . When HfO 2 enters the tumor tissues and is activated by external radiation beam, it can emit high energy electrons and increase the electron density deposited within irradiated tissues, resulting that the dose of X‐ray delivered to the tumor is magnified while the dose passing through healthy tissues remains unchanged.…”