Summary

Purpose/Objective(s): Concurrent chemoradiation (CRT) with high dose cisplatin or cetuximab in case of contra-indication to cisplatin is the standard of care non-surgical approach for patients (pts) with locally advanced head and neck squamous cell carcinoma (LA HNSCC). Older age is a contra-indication to cisplatin and survival in older pts might not improve with cetuximab. The development of new treatment options for elderly pts with LA HNSCC is therefore urgently needed. NBTXR3, hafnium oxide nanoparticles that enhance the efficacy of radiotherapy (RT) by locally increasing the deposited dose, may benefit this patient population. In this phase I clinical trial we aimed to evaluate the feasibility and safety of intratumoral (IT) NBTXR3 injection prior to RT in elderly pts with LA HNSCC.

Materials/Methods: Patients with stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based CRT received a single IT injection of NBTXR3 into a selected primary tumor followed by intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks) [NCT01946867]. The study used a 3+3 dose escalation design to test NBTXR3 dose levels of 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion at the Recommended Phase 2 Dose (RP2D). Primary endpoints included RP2D determination, and early dose limiting toxicities (DLT). NBTXR3 intratumoral bioavailability and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: Enrollment at all dose levels has been completed: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). There were no observed early DLT or SAE related to NBTXR3 or injection. Median follow-up from NBTXR3 administration is currently 7.6 months. One Grade 1 AE related to NBTXR3 at the 22% dose level and 4 Grade 1-2 AEs related to the injection at the 15% and 22% dose levels were observed. IMRT-related toxicity was as expected. NBTXR3 was well dispersed throughout the tumor and not in surrounding healthy tissues, as assessed by CT-scan. The RP2D was determined to be 22%. Preliminary efficacy was evaluated in pts who received the intended dose of NBTXR3 and RT. Among 13 evaluable pts at doses ≥10%, 9 pts (69%) achieved a complete response (2 unconfirmed) of the injected tumor and 5 pts (38%) achieved an overall complete response. Preliminary safety and efficacy data of the dose expansion cohort at the RP2D will also be presented.

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

Summary

In the treatment of head and neck squamous cell carcinoma (HNSCC), elderly and frail patients (pts) are ineligible for chemoradiation with cisplatin, the non-surgical standard of care. Consequently, innovative research tends toward a new treatment option, NBTXR3. These first-in-class hafnium oxide nanoparticles are activated by radiotherapy and physically destroy cancer cells. They are currently evaluated in a phase I clinical trial [NCT01946867] for locally advanced HNSCC in the population of interest.

At the ECHNO 2018 in Rome, Italy, preliminary results were presented and NBTXR3 resulted as safe and well tolerated even at the highest tested doses. Preliminary efficacy analysis suggests a promising perspective for the treatment of HNSCC in the elderly, with confirmed complete responses.

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

Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Metal elements offer specific characteristics due to their intrinsic properties and could be used in relation to their final state: a metal complex, a radionuclide, a metal-based nanoparticle product. Transition metal coordination complexes interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA. A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized radiation enhancers particles. The use of metals as a high electron density material tailored at the nanoscale when exposed to radiotherapy is a unique approach that can allow entry to the cell and make feasible the absorption/deposition of a high-energy dose within the tumor cell (on/off activity). Therefore, high electron density metal or metal oxide nanoparticles may bring well known physical mode of action, that of radiotherapy, within malignant cells and achieve the paradigm of local cancer treatment.

Summary

Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Transition metal coordination complexes offer potential advantages over the more common organic-based drugs, including a wide range of coordination number and geometries, accessible redox states, tunability of the thermodynamics and kinetics of ligand substitution, as well as a wide structural diversity. Metal-based substances interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA.

A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized particles. In this field, man-made functionalized nanoparticles of high electron density and well-defined size and shape offer the possibility of entering cancer cells and depositing high amounts of energy in the tumor only when exposed to ionizing radiations (on/off activity). These nanoparticles, such as hafnium oxide engineered as 50 nmsized spheres, functionalized with a negative surface (NBTXR3 nanoparticles), have been developed as selective radioenhancers, which represents a breakthrough approach for the local treatment of solid tumors. The properties of NBTXR3 nanoparticles, their chemistry, size, shape and surface charge, have been designed for efficient tumor cell uptake. NBTXR3 brings a physical mode of action, that of radiotherapy, within the cancer cells themselves. Physicochemical characteristics of NBTXR3 have demonstrated a very promising benefit-risk ratio for human healthcare across a broad non-clinical program. NBTXR3 has entered clinical development in therapy of advanced soft tissue sarcomas and head and neck cancer.