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

Background: Cancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3 , administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders.

Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; H&N) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2; lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile.

Results: To date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naïve) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented.

Conclusions: To date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naïve, as well as in patients having progressed on previous anti-PD-1 therapy will be presented.

Summary

Background: Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge immuno-oncology is facing. Intense efforts are being made to identify combination therapies that could improve ICI response rates. Administered intratumorally, NBTXR3 enhances the energy dose deposited by ionizing radiation within tumor cells, increasing the anti-tumor efficacy of radiation therapy (XRT) without adding toxicity to surrounding tissues. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients.

Methods: Abscopal assays were conducted in immunocompetent mice. Tumor cell lines, sensitive or resistant to anti-PD-1, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates were analyzed by immunohistochemistry (IHC).
Separately, in the phase II/III randomized trial Act.in.Sarc [NCT02379845] patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by wide tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers.
The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic ablative radiotherapy (SABR) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339].

Results: Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response a not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Tumor samples from the NBTXR3+XRT group also displayed increased PD-1+ cell density. Furthermore, in combination with anti-PD-1, NBTXR3+XRT improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as resulted in reduced number of spontaneous lung metastases. Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor response in patients who progressed on prior anti-PD-1.

Conclusions: The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field.

Summary

Purpose/Objective: Elderly and frail patients (pts) with head and neck squamous cell carcinoma (HSNCC) remain a challenging population to manage due to the lack of evidence-based recommendations. Despite representing approximately 20% of the HNSCC population no consensus exists on the optimal treatment for these pts with locally advanced (LA) disease, vulnerable to current standard of care treatment-induced toxicities. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3 hafnium oxide nanoparticles injected intratumorally may represent such an option. Otherwise inert, this first-in-class radioenhancer augments the radiotherapy (RT) dose within tumor cells when activated by RT, increasing tumor cell death compared to RT alone. The results presented here demonstrate the feasibility and safety of NBTXR3 activated by RT in elderly patients, a population with few therapeutic options.

Material/Methods: Patients with Stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based chemoradiation received a single intratumoral injection of NBTXR3 and intensity modulated radiation therapy (IMRT; 70 Gy/35 fractions/7 weeks). This is a 3+3 design dose escalation study to test NBTXR3 dose levels equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume, followed by a dose expansion. Primary endpoints include Recommended Phase 2 Dose (RP2D) determination and early dose limiting toxicities (DLT). NBTXR3 presence in surrounding healthy tissues and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: 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 injection were observed. One G1 AE (asthenia; 22%) related to NBTXR3 and four AEs (G2 oral pain, G1 tumor hemorrhage, asthenia, and injection site hemorrhage) related to injection were observed. RT-related toxicity was as expected with IMRT. The RP2D was determined to be 22% by the DSMB. CT-scan assessment demonstrated localization of NBTXR3 intratumorally without presence in surrounding healthy tissues. At a median follow-up of 231 days, 9/13 (2 unconfirmed) evaluable pts receiving doses ≥10%, achieved a complete response of the treated tumors. The final dose escalation safety and efficacy results will be presented herein.

Conclusion: NBTXR3 was well tolerated at all tested doses and demonstrated preliminary anti-tumor activity. The dose expansion part at the RP2D is ongoing. These results highlight the potential of NBTXR3 as a novel treatment option for elderly pts with LA HNSCC and address an unmet medical need.

Summary

Purpose/Objectives: Concurrent chemoradiation (CRT) with high dose cisplatin or cetuximab in case of contra-indication to cisplatin is the standard of care non-surgical approach for patients (pts) with locally advanced head and neck squamous cell carcinoma (LA HNSCC). Older age is a contra-indication to cisplatin and survival in older pts might not improve with cetuximab. The development of new treatment options for elderly pts with LA HNSCC is therefore urgently needed. NBTXR3, hafnium oxide nanoparticles that enhance the efficacy of radiotherapy (RT) by locally increasing the deposited dose, may benefit this patient population. In this phase I clinical trial we aimed to evaluate the feasibility and safety of intratumoral (IT) NBTXR3 injection prior to RT in elderly pts with LA HNSCC.

Materials/Methods: Patients with stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based CRT received a single IT injection of NBTXR3 into a selected primary tumor followed by intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks) [NCT01946867]. The study used a 3+3 dose escalation design to test NBTXR3 dose levels of 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion at the Recommended Phase 2 Dose (RP2D). Primary endpoints included RP2D determination, and early dose limiting toxicities (DLT). NBTXR3 intratumoral bioavailability and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: Enrollment at all dose levels has been completed: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). There were no observed early DLT or SAE related to NBTXR3 or injection. Median follow-up from NBTXR3 administration is currently 7.6 months. One Grade 1 AE related to NBTXR3 at the 22% dose level and 4 Grade 1-2 AEs related to the injection at the 15% and 22% dose levels were observed. IMRT-related toxicity was as expected. NBTXR3 was well dispersed throughout the tumor and not in surrounding healthy tissues, as assessed by CT-scan. The RP2D was determined to be 22%. Preliminary efficacy was evaluated in pts who received the intended dose of NBTXR3 and RT. Among 13 evaluable pts at doses ≥10%, 9 pts (69%) achieved a complete response (2 unconfirmed) of the injected tumor and 5 pts (38%)achieved an overall complete response. Preliminary safety and efficacy data of the dose expansion cohort at the RP2D will also be presented.

Conclusions: NBTXR3 was well tolerated at all tested doses and when activated by RT demonstrated promising preliminary anti-tumor activity. Recruitment in the dose expansion cohort is ongoing. These results highlight the potential of NBTXR3 activated by RT as a novel treatment option for elderly pts with LA HNSCC and address an unmet medical need.

Summary

Purpose/Objectives: Immune checkpoint inhibitors (ICIs) are being increasingly used to improve patient outcomes across different cancer types. However, the response rate to ICIs remains low (~15%), indicating the need for novel strategies to improve treatment outcome. Emerging evidence suggests that radiation therapy (RT) could potentially enhance the antitumor response and provide synergy with ICIs. RT dose and ultimate efficacy are however limited by toxicity related to exposure of healthy tissues. The first-in-class radioenhancer NBTXR3, administered by direct intratumoral injection, is designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing toxicity to surrounding normal tissue. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an 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 and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials/Methods: This multicenter, open-label, phase I trial [NCT03589339] will 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, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of baseline gross tumor volume (GTV).

Results: The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), 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, as well as mRNA and cytokine immune marker profiling. Recruitment is ongoing. To date, three patients have been treated, one in cohort 1 and two in cohort 2.

Conclusions: NBTXR3 activated by RT induces an anti-tumor immune response which may convert immunologically “cold” tumors into “hot” tumors. In combination R3/RT/PD-1 holds the potential to increase the proportion of ICI responders or convert ICI non-responders to responders.

Summary

Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. 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 direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an 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 and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders.

Method: This trial [NCT03589339] is a multicenter, open-label, phase I 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, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), 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, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2.

Summary

Purpose/Objectives: Elderly and/or frail patients (pts) with head and neck squamous cell carcinoma (HSNCC) remain a challenging to manage and neglected population regarding clinical trials and data generation to support treatment choices. Despite representing 20% of the HNSCC population no consensus exists on what is the optimal treatment for these pts with locally advanced (LA) disease, vulnerable to treatment-induced toxicities with the current standard of care. New approaches are needed to improve clinical outcomes without adding toxicity. NBTXR3 hafnium oxide nanoparticles injected intratumorally may represent such an option. Otherwise inert; this first-in-class radioenhancer, augments the radiotherapy (RT) dose within tumor cells when activated by RT, increasing tumor cell death compared to RT alone. The results presented here demonstrate the feasibility and safety of NBTXR3 activated by RT in elderly/frail patients, a population with few therapeutic options.

Material/Methods: Elderly/frail 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 theoretical tumor volume, followed by a dose expansion. Primary endpoints include Recommended Phase 2 Dose (RP2D) determination and early dose limiting toxicities (DLT). NBTXR3 presence in surrounding healthy tissues and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: 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 injection were observed. One G1 AE (asthenia; 22%) related to NBTXR3 and four AEs (G2 oral pain, G1 tumor hemorrhage, asthenia, and injection site hemorrhage) related to injection were observed. RT-related toxicity was as expected with IMRT. The RP2D was determined to be 22%. CT-scan assessment demonstrated localization of NBTXR3 intratumorally without presence in surrounding healthy tissues. At a median follow-up of 231 days, 9/13 (2 unconfirmed) evaluable pts receiving doses ≥10%, achieved a complete response of the treated tumors. The final dose escalation safety and efficacy results will be presented herein.

Conclusion: NBTXR3 was well tolerated at all tested doses and demonstrated preliminary anti-tumor activity. A dose expansion phase at the RP2D is ongoing. These results highlight the potential of NBTXR3 as a novel treatment option for elderly/frail pts with LA HNSCC and address an unmet medical need.

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: 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.