NBTXR3 for the Treatment of Elderly Frail Patients with Locally Advanced HNSCC

Abstract

The incidence of head and neck squamous cell carcinoma (HNSCC) increases with age and is expected to increase in the next 20 years. Despite representing 20% of the HNSCC population, elderly patients (pts) cannot be treated like the rest of the population due to their vulnerability to treatment-induced toxicity and thus new therapies are required. NBTXR3 represents a new treatment option and is currently being evaluated clinically. The first in class hafnium oxide nanoparticles (NBTXR3) are activated by radiotherapy and enhance its effects, leading to the physical destruction of cancer cells. A Phase I/II trial [NCT01946867] is underway to evaluate NBTXR3 in elderly pts (>70 years and older) or frail patients with locally advanced HNSCC of the oral cavity and oropharynx ineligible for cisplatin or intolerant to cetuximab. The phase I results are presented here. Elderly or frail pts were treated with a single intratumoral injection of NBTXR3 and intensity modulated radiation therapy (IMRT; 70 Gy/35 fractions/7 weeks) and followed until disease progression, further anticancer therapy or study cut-off date. The study is a 3 + 3 dose escalation to test the NBTXR3 dose equivalent to 5%, 10%, 15%, and 22% of the baseline tumor volume, followed by a dose expansion. Primary endpoints include determination of the Recommended Phase 2 Dose (RP2D) and early dose limiting toxicity (DLT). The presence of NBTXR3 in surrounding healthy tissues and efficacy applying RECIST 1.1 principles were also evaluated. 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 the injection procedure were observed. One grade 1 AE (asthenia at 22%) related to NBTXR3 and four AEs (grade 2 oral pain, grade 1 tumor hemorrhage, grade 1 asthenia, and grade 1 injection site hemorrhage) related to the injection procedure were reported. RT-related toxicity was as expected with IMRT. The RP2D has been determined to be 22%. CT-scan assessment between 24h and 7 weeks post injection demonstrated the absence of NBTXR3 leakage in surrounding tissues. Among the 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion per investigator assessment. The final dose escalation results will be presented herein. NBTXR3 was well tolerated at all tested doses and demonstrated a very good safety profile. With the identification of the RP2D, a dose expansion phase has started. These results of this study highlight the potential of NBTXR3 as a novel treatment option for elderly and/or frail pts with locally advanced HNSCC and address an unmet medical need. NBTXR3 is currently being evaluated in 5 other clinical trials, including a phase II/III trial in soft tissue sarcoma [NCT02379845] and phase I/II trials in prostate [NCT02805894], liver [NCT02721056] and rectal cancers [NCT02465593].