NANORAY-103: Phase I/II trial of NBTXR3 activated by SBRT in patients with HCC and liver metastases

Summary

Purpose/Objective: The use of stereotactic body radiotherapy (SBRT) for the local control of unresectable hepatocellular carcinoma (HCC) or liver metastases (mets) is well tolerated but limited by the need to preserve liver function. Increasing energy deposit within the tumor without increasing toxicity in healthy tissues remains a major challenge in radiation oncology. NBTXR3 (hafnium oxide nanoparticles), a first-in-class radioenhancer when activated by RT augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with HCC or 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].

Material/Methods: The Phase I is a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 has been 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 determination of the RP2D and early DLTs. Secondary endpoints included the safety profile, liver disease scores evolution, and early efficacy by response rate (mRECIST/RECIST 1.1).

Results: Twenty pts have been treated. The dose levels of 10, 15, 22 and 33% are completed: 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%. The final (42%) dose escalation level is ongoing with 3 pts treated thus far. No early DLT has been observed. One SAE (G3 bile duct stenosis) related to NBTXR3 and RT occurred at the 22% dose level. Adverse events related to ITI or NBTXR3 were: G2 malaise at the 10% dose level, 2 G3 abdominal pain at 15%, G1 pleural effusion and G3 bile duct stenosis at 22% and G1 fatigue at 33%. No clinically meaningful changes in CPS and APRI were observed post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding healthy tissues. Best observed response in evaluable patients for HCC (n=8) were 5 CR, 3 PR and for mets (n=5) the results were: 4 PR, 1 SD.

Conclusion: Intratumoral injection of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 42% dose level. Recruitment at the 42% dose level is nearly finalized. Early efficacy results suggest NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer.