Summary

Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers.

Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected.

Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed.

Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan.

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

To improve radiotherapy (RT) in terms of tumor response and to reduce irradiation of healthy tissues, innovative therapeutic approaches are needed. In response, NBTXR3, injectable hafnium oxide nanoparticles, was developed for the treatment of solid tumors.

Once injected intratumorally, NBTXR3 can deposit high energy within tumors only when activated by an ionizing radiation source, like current standard RTs. Upon activation, the high energy radiation physically kills the tumor cells by triggering DNA damage and cell destruction improving clinical outcomes.

Since its first successful clinical evaluation in a completed phase I trial in patients with locally advanced soft tissue sarcoma, NBTXR3 is currently evaluated in numerous indications worldwide (EU, Asia, US).

NBTXR3 have shown promising results in non-clinical studies with marked antitumor efficacy and in clinical development in terms of safety and preliminary evaluations of efficacy. Considering the preliminary results of the 145 patients injected across all clinical trials, these first-in-class nanoparticles have already proven to be an encouraging innovative treatment in various types of tumors. The last patient of the phase II/III trial in STS was included and the results of this study regarding efficacy and safety will soon be disclosed.

Summary

With recent advances in radiation delivery techniques, an increasing number of cancer patients undergo radiotherapy. However, due to the non-targeted nature of radiotherapy, doses are limited by potential toxicity to surrounding normal tissue. Thus, a major challenge remains to develop new strategies to improve the tumor selectivity of radiation therapy. Nanobiotix has developed NBTXR3 – a hafnium oxide nanoparticle that can enter tumor cells and deposit high levels of energy in cells when exposed to ionizing radiation thereby increasing tumor-specific physical killing through DNA damage/cell destruction and enhancing the intratumoral immune profile.

At 2018 ESTRO, an overview of NBTXR3 was presented, describing its role in current 7 clinical trials.

Summary

The enclosed abstract was presented at the 13th Journées cancéropole Grand Sud-Ouest at Poitiers. The abstract Hafnium oxide nanoparticles as an emergent promising treatment for solid tumors describes how hafnium oxide nanoparticles were designed at the nanoscale in the form of crystalline 50nm-particles to efficiently absorb ionizing radiation and increase the radiation dose deposited – “hot spots” of energy deposit – from within the tumor cells for efficient cell killing.

Hafnium oxide nanoparticles (NBTXR3), administered as a single intratumoral injection and activated by radiotherapy, is currently evaluated in a phase II/III clinical trial in soft tissue sarcoma (STS) [NCT02379845], and in phase I/II clinical trials for head and neck [NCT01946867], prostate [NCT02805894], liver [NCT02721056; NCT02721056] and rectum cancers [NCT02465593]. So far, patients treated with NBTXR3 received radiotherapy as planned and showed a very good local safety profile.