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

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

Purpose/Objective(s): The medical community faces important challenges to treat liver cancer because of underlying disease. Reduction of healthy tissue irradiation while at the same time increasing energy dose deposit within tumor cells still constitutes a challenge in radiation oncology. NBTXR3, hafnium oxide nanoparticles, increase energy deposit inside tumor cells only when activated by ionizing radiation such as stereotactic body radiotherapy (SBRT) and thus increase tumor cell death compared to radiation alone. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the physical mode of action of NBTXR3, which does not engage liver and renal functions. A phase I/II clinical trial was conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056].

Materials/Methods: The Phase I part follows a 3+3 dose escalation design with dose levels of NBTXR3 corresponding to 10, 15, 22, and 33% of the baseline tumor volume. Pts were treated with a single NBTXR3 intralesional injection (ILI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days). Primary endpoints included identification of the recommended phase II dose(s) and early DLTs. Secondary endpoints included assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1).

Results: Four levels of the dose escalation part are finalized (n=17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15 and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33%. No NBTXR3 related early DLT or SAE were observed. Indeed only one NBTXR3 related AE (G1 fatigue at 33%) was reported. There were no significant changes in CPS or APRI post-treatment. CT-scan assessment demonstrated absence of NBTXR3 leakage in surrounding tissues. Among 7 evaluable HCC pts, best mRECIST target lesion responses were: 3 CR, 4 PR. Among 5 evaluable mets pts, best target lesion responses were: 2 PR, 1 SD, 2 PD.

Conclusion: NBTXR3 was well tolerated up to the 33% dose level and demonstrated a very good safety profile. The very good tolerance and preliminary anti-tumor effects have supported a protocol amendment to study an additional higher NBTXR3 dose level (42%). Indeed recent data reinforces this further escalation as OS and local control seem to depend on RT dose and tumor volume. Liver dysfunction is the limiting factor for treatment in these pts, hence, this innovative physics based approach may constitute a valuable solution for pts with unresectable liver tumors. NBTXR3 showed statistically superior efficacy over RT alone in a phase II/III trial in soft tissue sarcoma [NCT02379845] and is currently being evaluated in phase I/II trials: head and neck [NCT01946867; NCT02901483], prostate [NCT02805894] and rectal cancers [NCT02465593].

Summary

Introduction: The treatment of liver cancers is challenging in part due to the presence of underlying liver diseases. In patients unsuitable for surgery, interventional radiation oncology approaches, i.e. minimally invasive image-guided therapeutic procedures, offer new treatment opportunities and can achieve good local control. NBTXR3, hafnium oxide nanoparticles, administered via intratumoral injection, increases energy deposit inside tumor cells only when activated by ionizing radiation such as stereotactic body radiotherapy (SBRT) and thus increase tumor cell death compared to radiation alone. Indeed, NBTXR3 showed statistically superior efficacy over RT alone in a phase II/III trial in soft tissue sarcoma [NCT02379845] and is currently being evaluated in phase I/II trials: head and neck [NCT01946867; NCT02901483], prostate [NCT02805894] and rectal cancers [NCT02465593]. The innovative physical mode of action of NBTXR3, which does not engage liver and renal functions might thus be beneficial to patients (pts) with unresectable hepatocellular carcinoma (HCC) or liver metastasis (mets).

Methods: A phase I/II clinical trial is being conducted to evaluate NBTXR3 activated by SBRT in patients with unresectable HCC or liver mets [NCT02721056]. The Phase I part follows a 3 + 3 dose escalation design with dose levels of NBTXR3 corresponding to 10, 15, 22, 33 and 42% of baseline tumor volume. Pts are treated with a single NBTXR3 intralesional injection (ILI) followed by SBRT (45 Gy or 50Gy/3-5 fractions/5 to 15 days). Primary endpoints include determination of the recommended phase II dose(s) and early DLTs. Secondary endpoints include assessment of global safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and response rate (mRECIST/RECIST 1.1).

Results: Four levels of the dose escalation part are finalized (n = 17): 6 pts at 10% (2 SBRT doses tested due to organs constraints), 4 pts at 15 and 22% (due to fiducial displacement and ILI shift) and 3 pts at 33%. ILIs were successful and SBRT was delivered as planned with no observed DLT at any dose level. One NBTXR3-related AE (G1 fatigue at 33%), 4 ILI-related AE (G2 malaise, 10%; two G3 abdominal pain, 15% and G1 bilateral pleural effusion, 22%) and one bile duct stenosis (G3) related to cancer disease and possibly to RT coupled with NBTXR3 administration were reported. There were no significant changes in CPS or APRI post-treatment. CT scan assessment demonstrated absence of NBTXR3 leakage in surrounding tissues. So far, among 7 evaluable HCC pts, best mRECIST target lesion responses were: 3 CR and 4 PR. Among 5 evaluable liver mets pts, best target lesion responses were: 2 PR, 1 SD, and 2 PD.

Conclusions: NBTXR3 was well tolerated up to the 33% dose level and demonstrated a very good safety profile. The recruitment is ongoing at 42%. In patients with unresectable liver tumors and liver dysfunction limiting treatment options, the physics-based NBTXR3 mode of action may thus constitute a valuable solution.