Summary

Background: Cancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3, administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders.

Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; H&N) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2; lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile.

Results: To date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naïve) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented.

Conclusions: To date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naïve, as well as in patients having progressed on previous anti-PD-1 therapy will be presented.

Summary

Purpose/Objective: Elderly and frail patients (pts) with head and neck squamous cell carcinoma (HSNCC) remain a challenging population to manage due to the lack of evidence-based recommendations. Despite representing approximately 20% of the HNSCC population no consensus exists on the optimal treatment for these pts with locally advanced (LA) disease, vulnerable to current standard of care treatment-induced toxicities. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3 hafnium oxide nanoparticles injected intratumorally may represent such an option. Otherwise inert, this first-in-class radioenhancer augments the radiotherapy (RT) dose within tumor cells when activated by RT, increasing tumor cell death compared to RT alone. The results presented here demonstrate the feasibility and safety of NBTXR3 activated by RT in elderly patients, a population with few therapeutic options.

Material/Methods: Patients with Stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based chemoradiation received a single intratumoral injection of NBTXR3 and intensity modulated radiation therapy (IMRT; 70 Gy/35 fractions/7 weeks). This is a 3+3 design dose escalation study to test NBTXR3 dose levels equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume, followed by a dose expansion. Primary endpoints include Recommended Phase 2 Dose (RP2D) determination and early dose limiting toxicities (DLT). NBTXR3 presence in surrounding healthy tissues and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: Enrollment was completed at all dose levels: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). No early DLT or SAE related to NBTXR3 or injection were observed. One G1 AE (asthenia; 22%) related to NBTXR3 and four AEs (G2 oral pain, G1 tumor hemorrhage, asthenia, and injection site hemorrhage) related to injection were observed. RT-related toxicity was as expected with IMRT. The RP2D was determined to be 22% by the DSMB. CT-scan assessment demonstrated localization of NBTXR3 intratumorally without presence in surrounding healthy tissues. At a median follow-up of 231 days, 9/13 (2 unconfirmed) evaluable pts receiving doses ≥10%, achieved a complete response of the treated tumors. The final dose escalation safety and efficacy results will be presented herein.

Conclusion: NBTXR3 was well tolerated at all tested doses and demonstrated preliminary anti-tumor activity. The dose expansion part at the RP2D is ongoing. These results highlight the potential of NBTXR3 as a novel treatment option for elderly pts with LA HNSCC and address an unmet medical need.

Summary

Combination of NBTXR3 and cisplatin has been evaluated in vitro and in vivo. No specific toxicity was observed for the cells exposed only to NBTXR3. For the combined treatment, a marked and enhanced cell destruction when compared to the single agent. In vivo, NBTXR3 combined with low dose of cisplatin delayed tumor growth when compared to single agent cisplatin in combination with radiotherapy.

Summary

Purpose: 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).

Experimental Design: 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.

Results: 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.

Conclusion: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 1–10. 2016 AACR.

Summary

Aim: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular highenergy dose deposit. Materials & methods: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomicnumber nanoparticles and ionizing radiation with biological systems.

Results: Using the Monte Carlo simulation, these nanoparticles, when exposed to highenergy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation.

Conclusion: These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients.