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 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: 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

Purpose/Objective(s): Local interventional treatments of cancers include interventional radiology and radiotherapy (RT). NBTXR3, hafnium oxide nanoparticles, is deeply associated to both. Given as a single local administration it increases energy dose deposit inside tumor cells only when activated by ionizing radiation. Various interventional treatments have been used to treat cancers such as liver, lung, bone. Because entirely new therapies such as NBTXR3 are being introduced, implementation of interventional approaches is continuously growing.

Materials/Methods: NBTXR3 is being evaluated in soft tissue sarcoma (STS, extremity, trunk wall) [NCT02379845], head and neck (HN) [NCT01946867, NCT02901483], prostate [NCT02805894], liver [NCT02721056] and rectal cancers [NCT02465593]. NBTXR3 injected volume is a percentage of baseline tumor volume, and therefore heterogeneous. Image guidance allowed for accurate injection. Standard catheters, needles, and syringes were used for preparation and injection. Importantly, percutaneous needle positioning was done within the region to be irradiated to control potential seeding of cancer cells. NBTXR3 was then activated by IMRT (STS, HN), EBRT or combination brachytherapy/EBRT boost (prostate), SBRT (liver), IMRT or IMAT (rectum).

Results: Thus far, NBTXR3 has been administered to 171 patients by intratumoral/lesional, and intraprostate injections depending on indication. NBTXR3 injections have been demonstrated safe and very well tolerated. Local infection, ulceration or massive tumor necrosis were never observed. This has been confirmed by adequate application of treatment schedules, fitting planned irradiation onset 1 to 5 days post-injection. Importantly, grade 1 ecchymosis and hematoma at puncture site (needle entry) observed in few cases always resolved spontaneously and did not impact dosimetry. Indeed, change of tumor/lesion/prostate volume resolved when water (NBTXR3 vehicle) was drained via lymphatic system. So far, inflammatory response to injection procedure itself was mild. Concerning AEs, grade 3 pain was observed in conscious patients under local anesthesia with STS close to joints (limited extensibility), and in needle shift in injection within a subcapsular liver tumor.

Conclusion: Across 7 clinical trials involving tumors in extremity, trunk wall, liver, rectum, prostate and HN, NBTXR3 injection was well tolerated and demonstrated a very good safety profile. The savoir faire of interventional radiology for local treatment of cancers supported implementation of injection procedures with specific parameters according to anatomy. Intratumoral/lesional or intraprostate injection ensures optimum bioavailability at site of irradiation, protecting patients from systemic toxicity. Future clinical research will involve other anatomical sites such as lymph nodes and lung lesions [NCT03589339].

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].