Summary

Purpose: Despite tremendous results achieved by immune checkpoint inhibitors, most patients are not responders, mainly because of the lack of a pre-existing anti-tumor immune response. Thus, solutions to efficiently prime this immune response are currently under intensive investigations. Radiotherapy elicits cancer cell death, generating an antitumor-specific T cell response, turning tumors in personalized in situ vaccines, with potentially systemic effects (abscopal effect). Nonetheless, clinical evidence of sustained anti-tumor immunity as abscopal effect are rare.

Methods: Hafnium oxide nanoparticles (NBTXR3) have been designed to increase energy dose deposit within cancer cells. We examined the effect of radiotherapy-activated NBTXR3 on anti-tumor immune response activation and abscopal effect production using a mouse colorectal cancer model.

Results: We demonstrate that radiotherapy-activated NBTXR3 kill more cancer cells than radiotherapy alone, significantly increase immune cell infiltrates both in treated and in untreated distant tumors, generating an abscopal effect dependent on CD8+ lymphocyte T cells.

Conclusion: These data show that radiotherapy-activated NBTXR3 could increase local and distant tumor control through immune system priming. Our results may have important implications for immunotherapeutic agent combination with radiotherapy.

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: Stereotactic body radiotherapy (SBRT) is a well-tolerated and valuable alternative for patients with unresectable hepatocellular carcinoma (HCC) or liver metastases (mets) who are not eligible for standard treatment such as surgery, local ablation or chemoembolization. Yet, the energy dose delivered to the tumor is limited due to potential toxicity to healthy tissues and the need to preserve liver function. Thus, achieving local control in liver cancers remains a challenge. The first-in-class radioenhancer NBTXR3 (hafnium oxide nanoparticles), administered by intratumoral (IT) injection once prior to RT treatment, augments the energy dose deposit within tumor cells when activated by RT. The result is increased tumor cell death compared to RT alone without increasing radiation exposure to surrounding tissues. Patients with HCC or mets may benefit from this new approach. Here we report on a phase I/II study evaluating NBTXR3 activated by SBRT in these patients.

Methods: In the phase I part of the study [NCT02721056], five NBTXR3 dose levels equivalent to 10, 15, 22, 33, and 42% of baseline tumor volume are tested following a traditional 3+3 design. NBTXR3 is administered by IT injection followed by SBRT (45 Gy / 3 fractions / 5-7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints include determination of the recommended phase 2 dose (RP2D) based on the incidence of the early DLTs. Secondary endpoints include the safety profile, liver disease scores evolution, and early efficacy by target lesions response rate (mRECIST/RECIST 1.1).

Results: To date, 22 patients have been treated and the 4 first dose levels are completed with 6 patients at 10% (2 SBRT doses tested due to organ constraints), 4 patients each at 15% and 22% (due to fiducial displacement and incomplete injected dose) and 3 patients at 33%. The last dose level (42%) is ongoing with 5 patients treated so far. No early DLT has been observed at any dose level. Five AEs (3 G1-2; 2 G3) related to the injection and 4 AEs related to NBTXR3 (3 G1-2; 1 G3), including 1 SAE (bile duct stenosis, also related to RT) were observed. No grade 4-5 AEs were observed. CT-scan showed no leakage of NBTXR3 into surrounding healthy tissues and SBRT safety profile was as expected. No clinically meaningful changes in CPS and APRI were observed post-treatment. In patients evaluable for efficacy, best observed target lesion responses were 5 complete response and 3 partial response in HCC patients (n=8) and, 5 partial response and 1 stable disease in liver mets patients (n=6).

Conclusions: NBTXR3 intratumoral injection is feasible and NBTXR3 demonstrates a very good safety and tolerability profile thus far. Recruitment is nearly completed at the 42% dose level. Early efficacy results highlight the potential for NBTXR3 to improve the clinical outcomes of patients with unresectable primary or metastatic liver cancer.

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: NBTXR3, functionalized hafnium oxide nanoparticles, administered by intratumoral injection (ITI) and activated by radiotherapy (RT), such as stereotactic body RT (SBRT), increases energy deposit inside tumor cells and subsequently tumor cell death compared to RT alone, while sparing healthy tissues. This innovative approach, which does not engage liver and renal functions, might benefit patients (pts) with unresectable liver cancers.

Methods: Phase I/II clinical trial to evaluate NBTXR3 administered by ITI activated by SBRT(45 Gy / 3 fractions / 5-7 days or 50 Gy / 5 fractions / up to 15 days) in pts with hepatocellular carcinoma (HCC) or liver metastases [NCT02721056]. Phase I 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. Primary endpoints include Recommended Phase 2 Dose (RP2D) determination and early DLT incidence. Secondary endpoints include safety profile, liver disease scores evolution, and early efficacy by response rate (mRECIST/RECIST 1.1).

Results: Enrolment at all dose levels is complete, 23 pts treated: 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), 3 pts at 33% and 6 pts at 42%. No early DLT was observed at any dose level. 1 SAE (late onset G3 bile duct stenosis) related to NBTXR3 and RT occurred at 22%. No clinically meaningful changes in Child-Pugh score and APRI were observed post-treatment. There were 11 AEs related to NBTXR3 and/or ITI, of which grade 3 AEs were: 2 abdominal pain (ITI related) and 1 bile duct stenosis (NBTXR3 related) No grade 4-5 AEs were observed.
CT-scan showed NBTXR3 within tumor without leakage to healthy tissues. To date, the best observed responses assessed by MRI in target lesions from evaluable pts for HCC (n=11) were 5 CR, 5 PR, 1 SD and for metastases (n=7) 5 PR, 2 SD.

Conclusions: NBTXR3 has demonstrated a very good safety and tolerability profile in these patient populations. The RP2D has been determined to be 42% of tumor volume. Early efficacy results highlight the potential for NBTXR3 to address an unmet medical need in pts with unresectable primary or metastatic liver cancer.

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

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.