Summary

Purpose/Objective(s): 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.

Materials/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).

Conclusion: 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/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.

Summary

Background: Hafnium oxide nanoparticles, NBTXR3, increase the effect of radiotherapy (RT) by enhancing local energy dose deposit within tumor cells, resulting in increased cell death compared to the same dose of RT alone. NBTXR3 efficacy was demonstrated in a phase II/III study in soft tissue sarcoma (NCT02379845) and is currently evaluated in other solid tumors including liver cancers. The use of this radio enhancer is particularly relevant in liver cancer management, a difficult to treat heterogenous population, due to the presence of underlying liver dysfunction.

Methods: Phase I/II study of NBTXR3 activated by RT in patients (pts) with HCC (with/without portal vein tumor thrombus) or liver metastasis (mets) [NCT02721056]. The dose escalation part followed a 3+3 design with tested dose levels equivalent to 10%, 15%, 22% and 33% of baseline tumor volume. Patients were treated with a single intralesional injection (ILI) of NBTXR3 followed by Stereotaxic Body RT (SBRT: 45 Gy/3 fractions/5 to 7 days). Determination of recommended dose(s) and early dose limiting toxicities (DLT) were primary endpoints. 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: The 4 levels of ILI dose escalation were 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% were included. ILIs were successful and SBRT was delivered as planned with no observed DLT or NBTXR3-related SAE at all levels. Only one grade 1 AE (fatigue) related to NBTXR3 was reported at dose level 33%. No relevant change of CPS or APRI was observed over time. Among 7 evaluable HCC pts the best target lesion responses by mRECIST were: 3 CR and 4 PR and among 5 evaluable mets pts: 2 PR, 1 SD and 2 PD.

Conclusions: This study demonstrated the feasibility and good tolerance of the first in class NBTXR3 ILI. These results have supported a protocol amendment adding a higher dose of NBTXR3 (42% of the tumor volume). This innovative approach might constitute a valuable solution for patients with unresectable liver tumors and liver dysfunction.

Clinical trial information: NCT02721056

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

Background: Hafnium oxide nanoparticles, NBXTR3, were developed to increase the tumor-localized high energy deposit once activated by ionizing radiation such as stereotactic body radiotherapy (SBRT) and thus to increase tumor cell death compared to the same dose of radiation. NBTXR3 is characterized by a single intratumor/intralesional (IL) administration and fits into standard RT schedule with no change in patient’s flow, treatment protocol or equipment. Herein the preliminary results of a phase I/II clinical trial evaluating this combination in patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets).

Methods: HCC and liver mets patients were treated with an IL injection of NBTXR3 followed by SBRT (15 Gy*3 fractions). The phase I part of the trial follows a 3+3 dose escalation design at dose levels of NBTXR3 corresponding to 10%, 15%, 22%, 33% of the baseline tumor volume. This study aims primarily to identify the Recommended Dose and the incidence of early Dose Limiting Toxicities (DLTs) of NBTXR3 activated by SBRT. 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: Enrollment is at the last dose level, 33%, and completed at 10% (6 pts), 15% (4 pts) and 22% (4 pts). So far, no early DLTs nor severe adverse events related to NBTXR3 were observed. Both CPS and APRI did not reveal important variations in accordance to NBTXR3 low toxicity. The best observed target lesions responses, among 7 evaluable HCC pts for response (mRECIST), were: 3 complete responses, 3 partial responses (PR) and 1 stable disease (SD) and among 5 evaluable liver mets pts: 1 PR, 3 SD and 1 progressive disease (RECIST 1.1).

Conclusions: NBTXR3 is well tolerated at the 22% dose level with an overall positive safety profile. This innovative approach might constitute a valuable solution for pts with liver tumors beyond standard treatment lines. NBTXR3 was successful in a phase II/III in soft tissue sarcoma [NCT02379845] and is currently evaluated in head and neck [NCT01946867; NCT02901483], prostate [NCT02805894] and rectum cancers [NCT02465593].