Summary

Compared to younger individuals, elderly patients with head and neck squamous cell carcinoma (HNSCC) have limited therapeutic options. Despite representing approximately 47% of the affected population with an increasing incidence, older patients are underrepresented from HNSCC prospective clinical trials further limiting their therapeutic options.

Intensity-modulated radiation therapy (IMRT) represents a viable treatment. Yet, like with all radiation therapy (RT) techniques, the energy dose deposit to tumor cells is limited by the surrounding healthy tissues. Injectable hafnium oxide nanoparticles, NBTXR3, were developed to increase the deposited dose of ionizing radiation within tumor cells when activated by RT. This phase I clinical study evaluates NBTXR3 in the treatment of locally advanced HNSCC of the oral cavity and oropharynx in frail elderly patients ineligible for surgery and cisplatin, the non-surgical standard of care, or intolerant to cetuximab.

Overall, preliminary results show a very good safety profile with favorable signs of efficacy, indicating NBTXR3 as a promising future treatment for frail and elderly patients with locally advanced HNSCC burdened from limited therapeutic options.

Summary

Hepatocellular carcinoma (HCC) is the most widespread primary liver cancer. Liver metastasis (mets) are even more common with a wide range of malignancies. Management of both liver affections is a challenging task regarding toxicity toward liver functions. In response, NBTXR3, innovative injectable hafnium oxide nanoparticles activated by radiotherapy, was developed to increase the local deposit of energy within the tumor cells without negatively affecting the liver. It is currently evaluated in a phase I/II clinical trial to introduce the use of NBTXR3 with stereotactic body radiation therapy (SBRT) in patients with HCC or liver mets [NCT02721056].

Overall, current results observed a safe and well tolerated profile for NBTXR3 indicating an encouraging perspective in patients highly vulnerable to liver complications. This multidisciplinary study brought together the successful complex cooperation of several centers and of different medical disciplines to treat two types of liver affections with an innovative approach.

Summary

With recent advances in radiation delivery techniques, an increasing number of cancer patients undergo radiotherapy. However, due to the non-targeted nature of radiotherapy, doses are limited by potential toxicity to surrounding normal tissue. Thus, a major challenge remains to develop new strategies to improve the tumor selectivity of radiation therapy. Nanobiotix has developed NBTXR3 – a hafnium oxide nanoparticle that can enter tumor cells and deposit high levels of energy in cells when exposed to ionizing radiation thereby increasing tumor-specific physical killing through DNA damage/cell destruction and enhancing the intratumoral immune profile.

At 2018 ESTRO, an overview of NBTXR3 was presented, describing its role in current 7 clinical trials.

Summary

Management of Hepatocellular Carcinoma (HCC) and Liver Metastasis (mets) requires complementary expertise of multiple specialties. Treatment decisions are increasingly complex and physicians must face a wide range of underlying liver dysfunctions and concomitant malignancies. Among available treatments, stereotactic body radiation therapy (SBRT) is well-tolerated. Yet, like with all radiation therapy (RT) techniques, the energy dose deposit needs to be maximized in tumor cells without affecting the surrounding healthy tissues. For such purpose, nanoparticles of hafnium oxide, NBTXR3, were designed to effectively absorb ionizing radiation and augment the dose deposited within the tumor cells only when activated by RT.

The first two dose levels at 10% and 15% are completed with 6 and 4 patients respectively. Two patients are currently included at the third dose level at 22%. All currently recruited patients were treated by intralesional injection. No early D LTs nor adverse events (AE) related to NBTXR3 were observed. One grade 2 malaise and two grade 3 abdominal pain AEs were reported to be related to the injection procedure. No serious adverse events related to NBTXR3 nor to the injection procedure were observed. Dispersion and permanence assessments by CT scan confirmed NBTXR3 to stay within the tumor without negatively impacting liver functions nor the reliability of the image-guided radiation therapy. Investigator assessment on target lesions by mRECIST via MRI resulted with the following best observed responses of target lesions to date in 7 evaluable patients: 3 complete responses, 3 partial responses and 1 stable disease.

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

NBTXR3 administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in a phase I clinical trial for head and neck cancer [NCT01946867]. At the 2018 Multidisciplinary Head and Neck Cancers Symposium in Scottsdale Arizona, preliminary results were presented by prof. C. Le Tourneau.

So far, patients treated in phase I showed good local and systemic tolerance to the product up to the highest dose level and received radiotherapy as planned, confirming a very good local safety profile. Regarding the patients, the durability of response so far is superior to 13 months, with some patients at 16 and 22 months follow-up without recurrence.

NBTXR3 nanoparticles constitute a rising hope for head and neck cancer patients as it could lead to a decrease in the long-term adverse effects of RT and an improvement in quality of life, associated with strong locoregional control.

Summary

The physical mode of action of NBTXR3 may represent a breakthrough approach for the local treatment of liver cancers, as it does not engage liver and renal functions, i.e. nanoparticles are not metabolized and not excreted by kidney. A phase I/II trial has been implemented for the treatment of hepatocellular carcinoma and liver metastasis [NCT02721056].

At the 2018 Gastrointestinal Cancers Symposium (also known as ASCO-GI) at San Francisco (CA, USA), Dr. Chajon presented preliminary results on this study.

Overall, the injection of NBTXR3 was safe and well tolerated at these levels. Patients received the planned RT. No DLT occurred. Enrollment is now opened at the 22% level. NBTXR3 shows promising results in terms of safety and antitumor activity and is also currently evaluated in other six clinical studies.

Summary

Loco-regional control in head and neck cancer has been improved by combining radiotherapy (RT) with chemical agents, radiosensitizers and monoclonal antibodies. However, these associations come with challenging limitations in terms of pharmacology, local control, clinical outcome benefits or patient quality of life. In addition, high doses of radiation may result in several undesired reactions which underline the need for new therapeutic approaches.

Functionalized hafnium oxide nanoparticles (NBTXR3) is a new class of material with high electron density, designed in the form of crystalline 50nm-particles (HfO2-NP) to efficiently absorb ionizing radiation and allow the absorption/deposition of a high radiation dose within the cancer cells, to physically kill the cells and modify the tumor immune profile.

HfO2-NP (NBTXR3), administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in a phase I clinical trial for head and neck cancer [NCT01946867] in elderly and frail patients that cannot receive the standard of care.

At the 2017 THNO in Nice, France, prof. C. Le Tourneau presented preliminary results of NBTXR3 in patients suffering from HNSCC. The treatment was associated with a positive safety profile, and preliminary effiacy evaluation, the local Complete Response rate is 83% (dose level 15% and 22%), with a duration of response of 22 months.

Summary

The enclosed abstract was presented at the 2017 Connective Tissue Oncology Society Annual Meeting (CTOS), Maui, Hawaii. The abstract NBTXR3 Treatment Induces Antitumoral Immune Response in Human Soft Tissue Sarcoma describes how NBTXR3 activated by RT triggers an enhanced adaptive immune response and contributes to transform “cold” tumor into “hot” tumor.

Summary

Recent studies reported that radiotherapy could activate the cGAS-STING pathway, which plays a fundamental role in the immune response to cytoplasmic DNA, by activation of the transcriptional factor IRF3, leading to expression of interferon-beta. Moreover, cGAS-STING activation appears to be an important component for tumor resident Antigen-Presenting Cells activation, a crucial step for induction of CD8+ T cell response against tumor derived antigens.

In this study, it was observed the ability of radiotherapy-activated NBTXR3 to increase cGAS-STING pathway response, compared to radiotherapy alone.