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: 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: 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

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: 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

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: 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.