NBTXR3 radiation enhancing hafnium oxide nanoparticles: RP2D for the treatment of HCC and liver metastases

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 II 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.