Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients.

Abstract

6051 Background: The non-surgical standard of care (SOC) for the treatment of locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication to cisplatin. However elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from these SOC treatments and represent a high unmet need. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3, a novel radioenhancer, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by radiotherapy (RT).NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. We present here the results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population. Methods: Patients with stage III-IVA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST 1.1. Safety is also evaluated. Results: As of August 13, 2020, 43 patients have been treated in the phase I dose expansion part. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 - 222.3). At a median time of 7.8 months after NBTXR3 injection, the ORR of the primary lesion was 83.9% and the CRR 67.7% in the evaluable population for efficacy (N = 31). Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented. Conclusions: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial. Clinical trial information: NCT01946867.

Advances and applications of nanoparticles in cancer therapy

“…In 2019, the HfO 2 NPs radioenhancer (NBTXR3) was extensively tested clinically and received a CE certification as a medical device for the treatment of locally advanced soft tissue sarcomas. [662][663][664] Though promising, more efforts are required to further optimize radiosensitive nanomaterials with safe, good biocompatibility, and easy modification, so as to make them more effective clinical auxiliary RT tools.…”

Emerging Trends in Nano-Driven Immunotherapy for Treatment of Cancer

“…Several clinical trials are now underway since the past decade to ascertain the usefulness of nanoparticle-based immunotherapy independently or in combination with conventional immunotherapy to understand their efficacy in the treatment of cancer. A Phase I clinical trial is currently underway using crystalline Hafnium oxide nanoparticles that exhibit immune stimulating effects in addition to its radio-enhancing properties along with anti-PD1 for treatment of individuals suffering from any form of primary cancer and with lung or liver metastasis [ 169 ]. Another Phase I trial used nanoliposomes to deliver the microRNA-34a (miR-34a) mimic to suppress immunosuppressive tumour genes in individuals with solid tumours.…”

Nanoparticle therapy for head and neck cancers

“…Nanoparticles delivery of paclitaxel, cisplatin, and CpG-A DNA are being evaluated in phase II trials. www.co-oncology.com was 22% of the tumor volume and was used in the expansion cohort that had enrolled 52 patients as of March 2021 [18]. Complete and partial response of the target lesion was observed in 62.5 and 20%, respectively, of the 40 patients that were evaluable for efficacy, which is promising.…”

“…Grade III and IV radiotherapy-related SAE occurred in four patients and were as expected with radiotherapy in this population. The recommended dose of NBTXR3 was 22% of the tumor volume and was used in the expansion cohort that had enrolled 52 patients as of March 2021 [18]. Complete and partial response of the target lesion was observed in 62.5 and 20%, respectively, of the 40 patients that were evaluable for efficacy, which is promising.…”