Summary

Background: The standard of care non-surgical approach for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients (pts) is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication. Older age is a contra-indication to cisplatin, and cetuximab might not improve survival in older pts. It is therefore urgently needed to develop new treatment options for elderly pts with LA HNSCC. NBTXR3 are hafnium oxide nanoparticles that can enhance the efficacy of radiotherapy (RT) by increasing locally the deposited dose. In this phase I clinical trial we aimed to evaluate the feasibility and safety of NBTXR3 administered as intratumoral (IT) injection prior to RT in LA HNSCC elderly pts.

Methods: Pts with stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based chemoradiation received a single IT injection of NBTXR3 into a selected primary tumor and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks) [NCT01946867]. A 3+3 dose escalation design, tested NBTXR3 dose levels equivalent to 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion at the Recommended Phase 2 Dose (RP2D). Primary endpoints included RP2D determination, and early dose limiting toxicities (DLT). NBTXR3 intratumoral bioavailability and anti-tumor activity (RECIST 1.1) were also evaluated.

Results: Enrollment was completed at all dose escalation levels: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). No early DLT or SAE related to NBTXR3 or injection were observed. The median follow-up from NBTXR3 administration is 7.6 months. One AE (Grade 1) related to NBTXR3 and four AEs (Grade 1-2) related to the injection were observed. RT-related toxicity was as expected with IMRT. CT-scan assessment showed a good dispersion of NBTXR3 throughout the injected tumor and not in surrounding healthy tissues. The RP2D was determined to be 22%. Preliminary efficacy was evaluated in pts who received the intended dose of NBTXR3 and RT. A complete response of the injected lesion was observed in 9/13 (69%) evaluable pts at doses ≥10% (2 unconfirmed) and an overall complete response in 5/13 (38%) evaluable pts at doses ≥10%. Preliminary safety and efficacy data of the dose expansion cohort at the RP2D will also be presented.

Conclusion: NBTXR3 activated by RT was well tolerated at all tested doses and demonstrated promising preliminary anti-tumor activity. Recruitment is ongoing in the dose expansion cohort. These results demonstrate that further testing of NBTXR3 in this population is warranted.

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. The high electron density of the nanoparticles, when exposed to radiotherapy (RT), allow the absorption/deposition of a high radiation dose within the tumor cells, to physically kill the cells and possibly improve outcome. A phase I trial was implemented for the treatment of locally advanced HNSCC in patients (pts) older than 65 years who cannot receive cisplatin.

Methods: Pts received a single intratumor (IT) injection of NBTXR3, volume dose levels escalated at 5%, 10%, 15% and 22% of baseline tumor volume, followed by RT (IMRT, 70Gy/ 35 fractions / 7 weeks). Primary endpoints included feasibility of the IT implantation and safety. Secondary endpoints included IT residency of NBTXR3 using CT scan and RECIST 1.1 response.

Results: Enrollment was completed for volume 5%, 10%, and 15% (11 pts) and 1 patient at volume dose level 22%. Feasibility of the IT injection was confirmed. The treatment was easily administered, was safe with no SAE, or early DLT, which allowed the pts for completion of the planned RT schedule. Adverse events related to the injection procedure included grade 1-2 injection pain (1 pt), and tumor hemorrhage (1 pt). Results demonstrated that a single injection of NBTXR3 provides adequate bioavailability of NBTXR3 IT over seven weeks of RT. No leakage of NBTXR3 to the adjoining healthy tissues was observed. Preliminary results of antitumor activity according to RECIST 1.1 are presented below: 11 evaluable pts, 10 showed complete or partial response (RECIST 1.1) including, 1/5 complete response at dose levels ≤ 10% and 3/6 complete responses at dose levels > 10% Follow up results with duration of response and tolerance will be disclosed.

Conclusions: Injection of NBTXR3 was safe and well tolerated. All pts received the planned RT.

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.