3-Dimensional Volumetric Distribution and Dispersion Analysis of the Radioenhancer NBTXR3 in Various Solid Malignancies

Abstract

<h3>Purpose/Objective(s)</h3> NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral (IT) injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of RT without additional toxicity to surrounding healthy tissue. In addition, NBTXR3 has been shown to prime the adaptive immune response in cancer models, with clinical indication of systemic response. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas (STS) and is under investigation in multiple tumor types. Here we report on the feasibility and intra-tumor dispersion of IT NBTXR3 injection in patients with various solid malignancies, including STS, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), liver metastases, lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma. <h3>Materials/Methods</h3> In the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced STS received either NBTXR3+RT or RT alone followed by tumor resection. Elderly patients with HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab, received a single IT injection of NBTXR3 and IMRT [NCT01946867]. In a Phase I trial patients with HCC or liver metastases received an IT injection of NBTXR3 followed by SBRT [NCT02721056]. Safety and efficacy of NBTXR3 + SBRT in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers in the Phase I 1100 [NCT03589339] trial. In a phase I study evaluating NBTXR3 intra prostate injection patients with newly diagnosed Unfavorable Intermediate Risk (UIR) or High Risk (HR) prostate adenocarcinoma were treated with EBRT or brachytherapy boost and EBRT. <h3>Results</h3> IT injection in patients with STS, HNSCC, HCC, liver or lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma is feasible. There was no leakage of NBTXR3 observed in surrounding healthy tissues as assessed by CT scan. IT dispersion of NBTXR3 ranged from 4.9%-28.2% of tumor volume in patients, depending on tumor size, with treatment doses of NBTXR3 ranging from 5-22% in HNSCC, HCC, lung metastasis, STS, and prostate. Favorable signs of efficacy were observed among these patients indicating the potential for NBTXR3 to improve patient outcomes at the doses tested and with dispersion within the tumor of up to 28.3%. <h3>Conclusion</h3> IT injection of NBTXR3 is feasible and safe in multiple tumor types. NBTXR3 injection has shown favorable safety and is continuing to be assessed in several Phase I studies. NBTXR3 demonstrated efficacy in a Phase II/III study in patients with STS. and promising signs of efficacy have been observed in other tumor types. Future consideration of dispersion analysis may include association with response and possibly dose-painting with simultaneous integrated boost secondary to preferential NBTXR3 loading.