Hafnium oxide nanoparticles activated by SBRT for the treatment of hepatocellular carcinoma and liver metastasis: a phase I/II trial

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].