Summary

Purpose: This phase I study assessed the safety of first-in-class radioenhancer nanoparticles, NBTXR3, in elderly or frail patients with locally advanced head and neck squamous cell carcinoma (HNSCC), ineligible for chemoradiation.

Methods: Patients with stage III or IVA (American Joint Committee on Cancer (AJCC) guidelines, 7th edition, 2010) HNSCC of the oral cavity or oropharynx, aged ≥70 or ≥65 years and ineligible to receive cisplatin, amenable to radiotherapy (RT) with curative intent, received NBTXR3 as a single intratumoural (IT) injection followed by activation by intensity-modulated radiation therapy (IMRT; 70 Gy). The NBTXR3 dose corresponded to a percentage of the baseline tumour volume, measured by magnetic resonance imaging. The primary objectives were to determine the recommended phase II dose (RP2D), dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Safety and tolerability were assessed using National Cancer Institute CTCAE version 4.0. Antitumour activity was assessed by Response Evaluation Criteria in Solid Tumours 1.1.

Results: Nineteen patients were enrolled: 3 at the dose level of 5%, 3 at the dose level of 10%, 5 at the dose level of 15% and 8 at the dose level of 22% of the tumour volume. The MTD was not reached, and no DLTs or serious adverse event (SAEs) related to NBTXR3 were observed. Four adverse events related to NBTXR3 and/or the IT injection were reported (grade I–II). NBTXR3 remained in the injected tumour throughout RT, with no leakage in the surrounding healthy tissues. Specific RT-related toxicity was as expected with IMRT. The RP2D was determined as 22% baseline tumour volume. Preliminary signs of antitumour activity were observed.

Conclusion: Intratumoural injection of NBTXR3 followed by IMRT is feasible and demonstrated a good safety profile, supporting further evaluation at the RP2D in this patient population.

Summary

Purpose: Elderly head and neck squamous cell carcinoma (HSNCC) patients (pts) ineligible for standard of care treatment require new therapeutic approaches. NBTXR3, hafnium oxide nanoparticles, may represent such an option. NBTXR3 is activated by radiotherapy, enhancing its effects, leading to physical destruction of cancer cells. A Phase I/II trial [NCT01946867] is underway to evaluate NBTXR3 in elderly (≥70 years) or frail pts with HNSCC of the oral cavity and oropharynx ineligible for cisplatin or intolerant to cetuximab.

Method & Materials: Pts received a single intratumoral injection of NBTXR3 and intensity modulated radiation therapy (IMRT; 70 Gy/35 fractions/7 weeks). The study was a 3 + 3 dose escalation to test the NBTXR3 dose equivalent to 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion. Primary endpoints include Recommended Phase 2 Dose (RP2D) determination and early dose limiting toxicities (DLT). Presence of NBTXR3 in surrounding healthy tissues and efficacy (RECIST 1.1 principles) were also evaluated.

Results: Enrollment for the dose escalation phase 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, G1 asthenia, and G1 injection site hemorrhage) related to injection were reported. RT-related toxicity was as expected. The RP2D has been determined to be 22%. CT-scan assessment demonstrated absence of NBTXR3 in surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved complete response of the injected lesion. The final dose escalation safety results will be presented herein.

Conclusion: NBTXR3 was well tolerated at all tested doses and demonstrated a good safety profile. A dose expansion phase has started with the identified RP2D. NBTXR3 is currently being evaluated in a phase II/III trial in soft tissue sarcoma [NCT02379845] and phase I/II trials in prostate [NCT02805894], liver [NCT02721056] and rectal [NCT02465593] cancers.

Clinical Relevance & Application: The 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.

Summary

Introduction: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care. NBTXR3, hafnium oxide nanoparticles injected intratumorally, may represent an option. Otherwise inert, NBTXR3 augments the radiation therapy (RT) dose within tumor cells when activated by RT, increasing tumor cell death compared to RT alone.

Objectives: The purpose of this Phase I was to evaluate safety (dose limiting toxicity; DLT) and determine the NBTXR3 recommended phase 2 dose (RP2D) in elderly or frail HNSCC pts.

Methods: Eligible pts had stage III or IV HNSCC of oral cavity or oropharynx, were aged ≥70 years or ≥65 years and unable to receive cisplatin but eligible for RT [NCT01946867]. A 3+3 dose escalation design was employed, with NBTRX3 dose levels of 5%, 10%, 15% and 22% of baseline tumor volume. Following intratumoral NBTXR3 injection, pts received IMRT (70 Gy; 35 fractions/7 weeks). Primary endpoints were RP2D and DLT. Localization of NBTXR3 and preliminary efficacy (RECIST 1.1) were also evaluated.

Results and Conclusion: Dose escalation is complete; 19 pts received NBTXR3: 3 at 5%, 3 at 10%, 5 at 15% and 8 at 22%. No NBTXR3-related DLTs or SAEs were observed. Four related AEs were reported: one AE at 15% (G1 tumor hemorrhage) and 3 AEs at 22% (G2 oral pain; G1 asthenia, G1 injection site hemorrhage). IMRT toxicity was as expected and post-injection CT scan showed NBTXR3 localized within the injected tumor. DSMB determined RP2D to be 22%. Among 13 evaluable pts at doses ≥10%, 9 had a complete response of injected tumor. Results demonstrate that NBTXR3 activated by RT is a well-tolerated therapy with encouraging anti-tumor activity. RP2D expansion is ongoing. NBTXR3 may be an option for elderly or frail pts with locally advanced HNSCC.

Summary

Background: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care treatment. NBTXR3, a crystalline solution of hafnium oxide nanoparticles may represent such an option. Injected intratumorally, NBTXR3 enters tumor cells and yields an increased cell-localized energy deposit upon exposure to radiotherapy (RT), leading to increased tumor cell death compared to the same dose of RT alone.

Methods: Phase I study of NBTXR3 activated by RT in pts ≥70 years old or ≥65 years old and unable to receive cisplatin, eligible for exclusive RT with stage III or IV HNSCC of the oral cavity or oropharynx [NCT01946867]. A 3+3 dose escalation design was implemented with dose levels corresponding to 5%, 10%, 15% and 22% of baseline tumor volume, followed by an expansion phase. Pts received an intratumoral (IT) injection of NBTXR3 and intensity modulated RT (IMRT; 70 Gy/35fractions/7 weeks). Determination of Recommended Phase 2 Dose (RP2D) and Dose Limiting Toxicities (DLT) were primary endpoints of phase I. Absence of NBTXR3 leakage and preliminary efficacy using RECIST 1.1 principles were also evaluated.

Results: The doseescalation is complete. Nineteen pts were enrolled: 3 at 5%, 3 at 10%; 5 at 15% and 8 at 22% with no observed DLT or SAE related to NBTXR3 or IT injection. One grade 1 NBTXR3-related AE (asthenia at 22%) and four IT injection-related AE (grade 2 oral pain; grade 1 tumor hemorrhage; grade 1 asthenia, and grade 1 injection site hemorrhage) were reported. RT-related toxicity was as expected with IMRT. RP2D has been determined to be 22%. CTscan assessment between 24h and 7 weeks post-IT injection demonstrated absence of NBTXR3 leakage in the surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion.

Conclusions: These results show that NBTXR3 activated by RT is safe and well tolerated at all doses with preliminary encouraging efficacy results. It thus represents a promising future treatment for frail and elderly pts with locally advanced HNSCC with limited therapeutic options. Expansion phase has started at the RP2D.

Clinical trial information: NCT01946867

Summary

Purpose/Objective: Hafnium oxide nanoparticles, NBTXR3, were developed to augment tumor-localized high energy deposit once activated by ionizing radiation such as Intensity Modulated Radiation Therapy (IMRT) and thus to increase tumor cell death compared to the same dose of radiation. NBTXR3 is characterized by a single intratumoral (IT) administration and fits into standard radiotherapy schedule with no change in patient’s care pathway, treatment protocol or equipment. A phase I trial is currently evaluating NBTXR3 in elderly patients (pts) with locally advanced head and neck squamous cell carcinoma (HNSCC) of the oral cavity and oropharynx not eligible for cisplatin or intolerant to cetuximab [NCT01946867].

Material/Methods: In this phase I open-label, non-randomized trial, elderly frail pts (65 years and older) were treated with an IT injection of NBTXR3 followed by IMRT (70 Gy in 35 fractions over 7 weeks) with a follow-up period until disease progression or study cut-off date. The study was designed as a 3 + 3 escalation dose with tested NBTXR3 dose levels at 5%, 10%, 15% and 22% of baseline tumor volume. Primary endpoints included the determination of recommended dose and early dose limiting toxicity (DLT). Presence of NBTXR3 in the surrounding healthy tissues and efficacy as per RECIST 1.1 tumor response were also evaluated.

Results: The inclusion was completed at all dose levels 22% (7 pts), 15% (5 pts), 10% (3 pts) and at 5% (3 pts). All patients that completed the DLT evaluation period did not present any early DLTs or serious adverse events (SAEs) related to NBTXR3 or the injection procedure. So far, two AEs (asthenia, grade 1; pain, grade 2) related to NBTXR3 were reported in patients at the 22% dose level. Additionally, four AEs related to the injection procedure (tumor hemorrhage, grade 1; oral pain, grade 2; asthenia, grade 1, hemorrhage, grade 1) occurred in patients at the 15% and 22% dose levels.

Conclusion: NBTXR3 was well tolerated even at the highest dose with an overall positive safety profile. As the last dose level was reached, a dose expansion group will start in this clinical setting once the recommended dose is identified. These results open a promising perspective in frail HNSCC pts with advanced age, which is a population not often evaluated in clinical trials. NBTXR3 was also evaluated in a phase II/III clinical trial in soft tissue sarcoma [NCT02379845] with positive results and is currently being evaluated in prostate cancer [NCT02805894], liver cancer [NCT02721056], rectal cancer [NCT02465593] and recurrent/metastatic HNSCC or metastatic non-small cell lung cancer [NCT03589339].