Summary

Background: Most cancer patients present resistance to immune therapy; only approximately 15% of patients respond to immune checkpoint inhibitors (ICI). Strategies able to increase ICI response are thus of great interest. Radiotherapy (RT), by acting as an immunomodulator is a good candidate to increase the proportion of ICI responders. However, RT dose and ultimate efficacy are limited by potential toxicity to healthy tissues. NBTXR3, a first in class radioenhancer administered by intratumoral injection, has been designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor response yielding both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic effect sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.

Methods: NANORAY-1100 [NCT03589339] is a multicenter, open-label, phase 1 study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregionally recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases from any primary cancer eligible for anti-PD-1, or (3) Liver metastases from any primary cancer eligible for anti-PD-1. Approximately two-thirds of each cohort will be composed of anti-PD-1 non-responders and one-third will be anti-PD-1-naïve. NBTXR3 injection volume is based on a percentage of gross tumor volume (GTV) determined by central review. The primary objective is to determine R3/RT/PD-1 RP2D. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, mRNA and cytokine immune marker profiling.

Summary

Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056].

Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1).
Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD.

Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.

Summary

Background: The majority of cancer patients are resistant to immune therapy; only around 15% respond to immune checkpoint inhibitors (ICI). Thus, strategies able to increase ICI response are of great interest. Recent work suggests radiotherapy (RT) can act as an immunomodulator to increase the proportion of ICI responders and improve clinical outcomes. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by intratumoral injection, designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.

Trial Design: NANORAY-1100 [NCT03589339] is a multicenter, open-label, phase 1 study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases from any primary cancer eligible for anti-PD-1, or (3) Liver metastases from any primary cancer eligible for anti-PD-1. Approximately two-thirds of each cohort will be composed of anti-PD-1 non-responders. NBTXR3 injection volume is based on a percentage of gross tumor volume (GTV) determined by central review. The primary objective is to determine R3/RT/PD-1 RP2D. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, mRNA and cytokine immune marker profiling.

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

Purpose: First in class hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Given that RT can prime an anti-tumor immune response we hypothesized that this response could be enhanced by NBTXR3+RT in both animals and humans.

Method & Materials: Different abscopal assays in mice were conducted. Immunocompetent mice were injected in both flanks with murine tumor cells. Intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT of right flank tumors only. Tumor growth was followed and immune cell infiltrates were analyzed by immunohistochemistry (IHC). Some mice received anti-PD-1 injections and tumor growth was monitored. Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received either NBTXR3+RT or RT alone. Pts pre- and post-treatment tumor tissues were analyzed by IHC and Digital Pathology for immune biomarkers.

Results: Animal studies demonstrated that NBTXR3+RT induces an immune response which was not observed with RT alone. IHC showed significantly more CD8+ cells present in NBTXR3+RT treated and untreated tumors. Furthermore, NBTXR3+RT improved the effect of anti-PD-1. Similarly, increased CD8+ T cell infiltration pre- vs post-treatment was observed in tumor tissues from STS pts treated with NBTXR3+RT. An increase in biomarkers, including CD8, following NBTXR3+RT was also observed by IHC in tumor samples from STS pts compared to RT alone.

Conclusion: These results demonstrate that NBTXR3+RT induces a specific adaptive immune profile in both mice and STS pts. NBTXR3+RT also improved response to anti-PD-1 in mice, opening the potential for combination with immunotherapeutic agents in humans. We have therefore sought to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 in pts with locoregionally recurrent or metastatic (lung or liver) head and neck squamous cell carcinoma, as well as in metastatic non-small cell lung cancer and liver metastasis pts [NCT03589339].

Clinical Relevance & Application: The results of this study highlight the potential of NBTXR3 to be used in combination with immune checkpoint inhibitors in order to improve patient outcomes.

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

Objectives: A subset of locally advanced soft tissue sarcoma (STS) patients achieve significant therapeutic benefit from preoperative radiation therapy (RT) as shown by Pisters JCO 1996 and Yang JCO 2018. However, the impact of RT on pathological response (pR) and R0 resection is limited, highlighting the need for novel multimodal therapies aimed at local control. NBTXR3 (hafnium oxide nanoparticles), injected intratumorally may represent such an option. Otherwise inert, NBTXR3 augments the effective RT dose deposited within tumor cells when activated by ionizing radiation to increase cancer cell death compared to RT alone. We report here on the results of a phase II/III randomized clinical trial evaluating the preoperative efficacy and safety of NBTXR3 activated by RT in patients with locally advanced STS of the extremity and trunk wall [NCT02379845].

Methods: This is a multi-national phase II/III randomized, open-label clinical trial. Adults with locally advanced STS of the extremity or trunk wall, of any histologic grade, eligible for preoperative RT were randomly assigned 1:1 to receive NBTXR3 as a single intratumoral injection (volume corresponding to 10% of baseline tumor volume at 53.3g/L) followed by external beam RT (EBRT; 50 Gy as 25 fractions of 2 Gy, over 5 weeks) (arm A) or EBRT alone (arm B). Both arms had the chance to go on to receive post-RT surgical resection. The primary objective was to compare the proportion of patients with pathological complete response (pCR; defined as <5% of residual viable cancer cells after surgery), as assessed by a Central Pathology Review Board based on the EORTC guidelines. Key secondary endpoints included negative surgical margin (R0), limb amputation rate and safety. Safety was evaluated in all subjects who received at least one puncture of NBTXR3 or at least one fraction of RT. Subjects are in continued long-term follow-up, focused on safety.

Results: Between March 3rd, 2015 and November 21st, 2017, 180 patients were randomized and 179 received treatment: n=89; arm A and n=90; arm B. The proportion of patients with pCR was 16.1% (14/87) compared with 7.9% (7/89) in arms A and B, respectively (p=0.044). The R0 resection rate was 77.0% (67/87) in arm A versus 64.0% (57/89) in arm B (p=0.0424). The most common grade 3-4 treatment emergent adverse event (AE) was post-operative wound complication, which occurred at a similar rate in each arm (8/89 and 8/90 in arm A and B, respectively). The most common grade 3-4 AE related to NBTXR3 administration was injection site pain (4/89, 4.5%) and hypotension (4/90, 4.4%). Skin injury was the most common grade 3-4 RT-related AE, which was shared between both arms (5/89, 5.6% and 4/90, 4.4% in arm A and B, respectively). Serious AEs were observed in 35 (39.3%) of 89 patients in arm A and 27 (30.0%) of 90 patients in arm B. There were no treatment-related deaths. Follow-up was conducted on 153 patients with a current median follow-up of 18.5 months. Currently 87 patients are still in long-term follow-up.

Conclusion: This registration trial of NBTXR3 combined with EBRT significantly achieved its primary and secondary endpoints of improving pCR, and increasing R0 resection versus EBRT alone. NBTXR3 together with EBRT was well tolerated with a safety profile consistent with EBRT alone. Taken together, these results led to the EU approval (CE Mark) of NBTXR3 + RT for patients with locally advanced STS of the extremity and trunk wall.

Summary

Background: Treatment of hepatocellular carcinoma (HCC) and liver metastasis (mets) is challenging due to presence of underlying disease, e.g. cirrhosis. Stereotactic body radiation therapy (SBRT) is a well-tolerated alternative for inoperable patients (pts), yet maximal dose to the tumor is limited by potential toxicity to surrounding healthy tissues. Otherwise inert, NBTXR3 (hafnium oxide nanoparticles) when activated by ionizing radiation (RT) augments dose deposit within tumor cells, increasing tumor cell death compared to RT alone. A phase I/II clinical trial is underway to evaluate NBTXR3 activated by SBRT in pts with HCC or liver mets [NCT02721056].

Methods: A 3 þ 3 dose escalation was utilized in the phase I. Pts received a single intralesional injection (ILI) of NBTXR3 followed by SBRT (45 Gy/3 fractions/5-7 days), with tested NBTXR3 dose levels of 10, 15, 22 and 33% of baseline tumor volume. Primary endpoints included recommended phase II dose(s) identification and DLT.
Secondary endpoints included global safety profile assessment, liver function by ChildPugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST v1.1).

Results: Four dose escalation levels are finalized (n ¼ 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts at 15 and 22% (due to fiducial displacement and ILI site shift) and 3 pts at 33%. No NBTXR3 related DLTs were observed. Related AEs observed: one malaise (G2, 10%); 2 abdominal pain, (G3, 15%); one bilateral pleural effusion (G1, 22%), one bile duct stenosis (G3, 22%) with associated disease recurrence and SBRT; one fatigue (G1, 33%). There were no clinically meaningful changes to CPS or APRI and CT-scan demonstrated absence of NBTXR3 in surrounding healthy tissues. In 7 evaluable HCC pts, best mRECIST target lesion responses were: 3 CR, 4 PR. In 5 evaluable mets pts, best target lesion responses were: 2 PR, 1 SD, 2 PD.

Conclusions: NBTXR3 was well tolerated and showed preliminary anti-tumor activity, supporting a protocol amendment to evaluate an additional NBTXR3 dose level (42%). This innovative approach has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver lesions.

Clinical trial identification: NCT02721056.

Summary

Doubling complete histological response in sarcomas with radiation therapy using nanoparticles (Hafnium oxide, NBTXR3), a phase III trial

Summary

NBTXR3, injectable hafnium oxide nanoparticles, was designed to increase the energy deposit of the irradiation when activated by radiotherapy for the treatment of solid tumors. It is currently evaluated in a phase II/III clinical trial in soft tissue sarcoma (STS) [NCT02379845] of the extremity and trunk wall, to compare its efficacy when intratumorally injected and activated by radiotherapy versus radiotherapy alone. In this study, treatment planning depends on the Gross Tumor Volume (GTV) and dosimetric calculations, measured before injection of NBTXR3. A change in the GTV volume during radiotherapy treatment could impact the dosimetric coverage. In order to evaluate this change in GTV volume during radiotherapy treatment an ancillary study was put in place.

NBTXR3 nanoparticles are activated by current standard radiotherapy without changing the applied dose and to increase the probability of interaction with incoming radiations to ameliorate the energy dose deposition from within tumor cells. The results of this study on the modifications of volumes during the radiotherapy treatment and their potential dosimetric impact will allow an objective evaluation of the dosimetric coverage all along the treatment period.