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

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

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

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

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

Clinical trial information: NCT01946867

Summary

Purpose/Objective: Patients with hepatocellular carcinoma (HCC) and liver metastasis (mets) present with a wide range of underlying liver dysfunctions and concomitant malignancies. Stereotactic body radiation therapy (SBRT) is well-tolerated and a valuable alternative for patients who are not eligible for invasive procedures. Yet, like all radiation therapy (RT) techniques, the energy dose deposit to tumor cells is limited by the surrounding healthy tissues. NBTXR3, composed of hafnium oxide nanoparticles, was designed to effectively absorb ionizing radiation and augment the dose deposit within the tumor cells only when activated by RT, thereby increasing tumor-specific physical killing through DNA damage/cell destruction and enhancing the immunogenic tumor cell death.

Material/Methods: Patients suffering from primary HCC (with/without portal vein tumor thrombosis) or liver mets were included and treated with a single intralesional injection (IL) of NBTXR3 followed by SBRT (45 Gy/3 fractions/5 to 7 days). The phase I part of the study was designed as a 3 + 3 escalation dose with tested dose levels at 10%, 15%, 22% and 33% of baseline tumor volume. Primary endpoints include the determination of the recommended dose and incidence of early dose limiting toxicities (DLTs). Secondary endpoints include assessment of global safety profile, characterization of the body kinetic profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST v1.1).

Results: The enrollment is complete in the first 3 dose levels: 10% (6 pts), 15% (4 pts) and 22% (4 pts) and is ongoing at the last IL dose level at 33% with no early DLTs, no AE related to NBTXR3, and no serious AE related to RT or the injection. So far, four AEs related to the IL were observed (Malaise, grade 2; two Abdominal pain, grade 3 and Bilateral pleural effusion, grade 1) at dose level 10%, 15% and 22% respectively. NBTXR3 remained localized within the tumor, validating the relevance of the single IL. No relevant change in CPS or APRI was observed over time which is consistent with the low toxicity observed. In 7 HCC pts evaluable for response, the mRECIST assessment by MRI on target lesions resulted in the following best observed response: 3 complete responses, 3 partial responses and 1 stable disease. In 5 evaluable liver mets pts, the RECIST v1.1 assessment by MRI on target lesions resulted in the following best observed response: 1 partial response, 3 stable disease and 1 local progressive disease.

Conclusion: NBTXR3 was well tolerated and showed a promising safety profile. Recruitment at the highest dose level of 33% is ongoing for the IL part and, once completed, will be followed by the expansion phase. NBTXR3 is also being evaluated in 6 other clinical trials, including a phase II/III trial in soft tissue sarcoma [NCT02379845] and phase I/II trials in prostate [NCT02805894], head and neck [NCT01946867] and rectum cancers [NCT02465593].

Summary

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

Summary

Background: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2–3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma.

Methods: Act.In.Sarc is a phase 2–3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0–2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete.

Findings: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group.Two patients
in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3–4 reatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3–4 adverse events related to NBTXR3 administration were
injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3–4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3–4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred.

Interpretation: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers.