Summary

Radiotherapy has a universal and predictable mode of action, that is, a physical mode of action consisting of the deposit of a dose of energy in tissues. Tumour cell damage is proportional to the energy dose. However, the main limitation of radiotherapy is the lack of spatial control of the deposition of energy, that is, it penetrates the healthy tissues, damages them and renders unfeasible delivery of an efficient energy dose when tumours are close to important anatomical structures. True nanosized radiation enhancers may represent a disruptive approach to broaden the therapeutic window of radiation therapy.

They offer the possibility of entering tumour cells and depositing high amounts of energy in the tumour only when exposed to ionizing radiations (on/off activity). They may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumour structure without passing through surrounding tissues feasible. Several nanosized radiation enhancers have been studied in in vitro and in vivo models with positive results. One agent has received the authorization to conduct clinical trials for human use. Opportunities to improve outcomes for patients receiving radiotherapy, to create new standards of care and to offer solutions to new patient populations are looked over here.

Summary

Background: Functionalized hafnium oxide nanoparticles (NBTXR3) have been developed as selective radioenhancers, which may represent a breakthrough approach for the local treatment of solid tumors. This is a unique approach where crystalline nanomaterials with high electron density when exposed to radiotherapy, can allow penetrate into the cell and make feasible the absorption/deposition of a high energy dose within the tumor cell. A phase I/II trial was implemented in patients with locally advanced STS.

Methods: Patientsreceived a single intratumor (IT) injection of NBTXR3, volume escalated, followed by 50Gy RTx. Primary endpoints include feasibility of the IT implantation and safety. Secondary endpoints focus on efficacy such as pathological and RECIST response, IT residency of NBTXR3 over all the RTx period and operability. Results: Enrollment was completed for volume 1, 2, and 3 (15 pts). Feasibility of the IT injection was confirmed. The treatment was safe with no SAE, no early DLT and allowed the pts for completion of the planned RTx schedule. No grade 3-4 toxicity occurred, main grade 1-2 toxicities related to NBTXR3 were injection pain/reaction (4 pts), pyrexia (2 pts), abdominal pain (1 pt), pruritus (1 pt) and paresthesia (1 pt). Results demonstrated that a single injection of NBTXR3 provides adequate bioavailability of NBTXR3 IT over five weeks of radiotherapy. No leakage of NBTXR3 to the adjoining healthy tissues was observed. Further, NBTXR3 persistence was established by CT scan before surgery.

Conclusions: Injection of NBTXR3 was well tolerated. All pts received the planned radiotherapy (50 Gy/25 fractions/ 5 weeks) followed by wide surgical resection of the sarcoma. NBTXR3 with RTx showed a very good safety profile. Encouraging signs of antitumor activity were observed in different sarcoma subtypes, such as undifferentiated sarcoma, rhabdomyosarcoma, and synovial sarcoma, which constitutes a promising feature for this subset of pts whose primary tumor is locally advanced and has an important risk of relapse. Clinical trial information: NCT01433068.

Summary

Full Title: NBTXR3 hafnium oxide nanoparticle activated by ionizing radiation demonstrates marked radioenhancement and antitumor effect via high energy deposit in human soft tissue sarcoma

Content: Local and systemic control of Soft Tissue Sarcoma (STS) remains a clinical challenge. Radiation therapy is part of the standard of care of STS. The narrowness of its therapeutic window represents the main concern for different clinical settings. Thus, local delivery of radiation doses is critical to ensure optimal benefit-risk ratio. NBTXR3, biocompatible hafnium oxide nanoparticles were designed as therapeutics to be activated by ionizing radiation to achieve tumor control by enhancement of local energy deposition.