Summary

Background: NBTXR3, a first-in-class radioenhancer composed of functionalized hafnium oxide nanoparticles, is administered by one time intratumoral injection (ITI) and activated by radiotherapy (RT), such as stereotactic body RT (SBRT). NBTXR3 increases RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. SBRT is well-tolerated in hepatocellular carcinoma (HCC) or liver metastases (mets) and a valuable alternative for patients not eligible for surgery or radiofrequency ablation. However, energy dose deposit to tumor cells is limited due to potential toxicity to surrounding healthy tissues. Patients with unresectable liver cancers including patients with liver or renal dysfunction might benefit from NBTXR3. A Phase 1 clinical trial was conducted to evaluate the safety and Recommended Phase 2 Dose (RP2D) of NBTXR3 activated by SBRT [NCT02721056] in these patients, here we report the results.

Methods: A 3+3 dose escalation scheme tested 5 NBTXR3 levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 ITI was followed by SBRT (45 Gy / 3 fractions / 5-7 days or 50 Gy / 5 fractions / up to 15 days) in patients with HCC or liver mets. Primary endpoints included RP2D determination and early DLT incidence. Secondary endpoints include safety profile, liver disease scores evolution, and early efficacy by response rate (mRECIST for HCC/RECIST 1.1 for liver mets).

Results: 23 patients were treated: 6 patients at 10% (2 SBRT doses tested due to organ constraints), 4 patients each at 15% and 22% (due to fiducial displacement and ITI shift), 3 patients at 33% and 6 patients at 42%. No early DLT was observed at any dose level. 1 SAE (grade 3 late onset bile duct stenosis) related to NBTXR3 and RT occurred at 22%. There were 11 AEs related to NBTXR3 and/or ITI, of which grade 3 AEs were: 2 abdominal pain (ITI related; 15%) and 1 late onset bile duct stenosis (22%), lesion close to the bile duct. No NBTXR3 or ITI related grade 4-5 AEs were observed. RT related AEs were as expected with SBRT. No clinically meaningful changes in Child-Pugh score or APRI were observed post-treatment. CT-scan showed NBTXR3 present within the tumor without leakage to surrounding healthy tissues. Best observed responses (MRI) in injected target lesions from HCC patients (n = 15) were 5 CRs (33.3%), 5 PRs(33.3%), 1 SD (6.7%), 2 NE (13.3%), 2 patients did not have post baseline MRI and for liver mets (n = 8) were 5 PRs (62.5%), 2 SD (25.0%) and 1 NE (12.5%).

Conclusions: No early DLTs were observed and NBTXR3 demonstrated a good safety and tolerability profile. The RP2D was determined to be 42% of tumor volume. Initial efficacy is promising and highlights the potential for NBTXR3 to address an unmet medical need in patients with unresectable primary or metastatic liver cancers.

Summary

Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers.

Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected.

Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed.

Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan.

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

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

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].

Materials/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.

Conclusion: 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.

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 and 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: 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

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+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 Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST v1.1).

Results: Four dose escalation levels are finalized (n=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.

Summary

Purpose/Objective(s): Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Currently 7 clinical trials are underway to evaluate NBTXR3+RT. To date, no dose limiting toxicities (DLTs) have been observed. 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.

Materials/Methods: Immunocompetent mice were injected in both flanks with CT26 cells. An intratumoral injection of NBTXR3 (or vehicle) was performed in right flank tumors, followed by RT (3x4Gy). Tumor growth was followed, and animals sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Pts with locally advanced soft tissue sarcoma (STS) [NCT02379845] received either NBTXR3+RT or RT alone. Pre- and post-treatment tumor tissues (biopsy and tumor resection respectively) from pts were analyzed by IHC and Digital Pathology for immune biomarkers (>16 pts per arm).

Results: Animal studies demonstrated that NBTXR3+RT can induce an immune response which was not observed with RT alone. IHC analyses showed that significantly more CD8+ cells were present in NBTXR3+RT treated and untreated tumors, compared to tumors from mice treated with RT alone. 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 and PD1, 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. As such, it may convert immunologically “cold” tumors into “hot” tumors, opening the potential for combination with immunotherapeutic agents. 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 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) head and neck squamous cell carcinoma (HNSCC), as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

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.