Donnée clinique de NBTXR3 | Nano Publications

2021 – A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients

nano-pub — Fri, 27 May 2022 11:12:04 +0000

Authors

C. Le Tourneau, V. Calugaru, V. Moreno, E. Calvo, X. Liem, S. Salas, B. Doger, T. Jouffroy, X. Mirabel, J. Rodriguez, A. Chilles, K. Bernois, N. Fakhry, S. Wong Hee Kam, C. Hoffmann

Summary

Introduction: Non-surgical standard of care (SOC) for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is chemoradiation with cisplatin/cetuximab. Elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from current SOC, representing a high unmet need. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is activated by radiotherapy (RT). NBTXR3 increases RT energy deposit in tumor cells and subsequent tumor cell death, while sparing healthy tissues compared to RT alone. NBTXR3 subsequently primes an adaptive immune response.

Objectives: The phase I dose expansion study aims to evaluate safety and efficacy of NBTXR3 + RT in patients with stage III–IVA or T3/T4 (TNM-8) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT.

Methods: Patients received a single intratumoral injection of NBTXR3 + RT (70 Gy, 35 fractions/7 weeks). A 3 + 3 dose escalation design tested four NBTXR3 doses: 5, 10, 15, and 22% of baseline theoretical tumor volume; and established RP2D as 22%. Primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor (RECIST 1.1).

Results and Conclusion: As of March 26, 2021, 52 patients were treated in the dose expansion part. Median age and tumor volume were 71.6 years and 60.6 mL respectively. ORR of the primary lesion was 82.5% and CRR was 62.5% (N = 40) at a median of 8.1 months after NBTXR3 injection. RT-related toxicity was as expected. Six patients experienced at least one G3–4 serious adverse event (AE) related to injection procedure and/or NBTXR3 (< 1% of all AEs). Four deaths related to RT were observed, also one death from sepsis possibly related to NBTXR3, RT, and cancer disease was reported. NBTXR3 + RT showed promising efficacy, supporting further evaluation in a phase III randomized trial.

The post 2021 – A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients first appeared on Nano Publications.

2021 – Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial

nano-pub — Fri, 27 May 2022 10:06:03 +0000

Authors

S.Bonvalot1, P.Rutkowski2, J.O.Thariat3, S.Carrere4, A.Ducassou5, M.P.Sunyach6, P.Ágoston7, A.Hong8, A.Mervoyer9, M.Rastrelli10, C.LePechoux11, V.Moreno12, R.Li13, B.Tiangco14, Z.Papai15

1 – Curie Institute, Paris, France
2 – Centrum Onkologii-Instytut im. Sklodowskiej-Curie w Warszawie, Warszawa, Poland
3 – Centre François Baclesse, Caen, France
4 – Montpellier Cancer Institute, Montpellier, France
5 – Institut Claudius Regaud – IUCT Oncopôle, Toulouse, France
6 – Centre Leon Berard, Lyon, France
7 – National Institute of Oncology, Budapest, Hungary
8 – Melanoma Institute Australia, Sydney, NSW, Australia
9 – Institut de Cancerologie de l’Ouest-Rene Gauducheau, Saint-Herblain, France
10 – Istituto Oncologico Veneto IRCCS, Padova, Italy
11 – Institut Gustave Roussy, Villejuif, France
12 – Hospital Fundación Jimenez Diaz, Madrid, Spain
13 – St. Luke’s Medical Center, Quezon City, Philippines
14 – The Medical City Cancer Center, Pasay City, Philippines
15 – Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary

Summary

Purpose/Objective(s): NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; P = 0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; P = 0.042) were met while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Materials/Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT. Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the “all treated population” during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis, arthrosis and edema that may alter limb function showed no difference between arms (4.5% vs 7.7%, 2.2% vs 0.0% and 6.7% vs 2.2% respectively in A vs B). In addition, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. Finally, second primary cancer was observed in 1 patient in arm A and 6 patients in arm B and the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site.

Conclusion: These results demonstrate that the use of NBTXR3 did not change the late onset toxicity profile of EBRT, nor modified its bystander effect. Taken together, the long-term safety data presented here, and the previously published efficacy data reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. NCT02379845

The post 2021 – Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial first appeared on Nano Publications.

2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial

nano-pub — Fri, 27 May 2022 09:52:17 +0000

Authors

Colette Shen1, Jessica Frakes2, Jiaxin Niu3, Jared Weiss1, Jimmy Caudell2, Katherine Jameson4, Patricia Said4, Tanguy Seiwert5

1 – University of North Carolina School of Medicine;
2 – Moffitt Cancer Center;
3 – Banner MD Anderson Cancer Center;
4 – Nanobiotix;
5 – Johns Hopkins Medicine

Summary

Purpose/Objective(s): Immune checkpoint inhibitors (ICIs) have led to improved treatment outcomes in a variety of cancers; however, the majority of patients exhibit resistance to ICIs. Overcoming this resistance is a major challenge in immune-oncology. Radiation therapy (RT) has emerged as a promising combination with ICIs since it may act synergistically with ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposit inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials/Methods: This multicenter, open-label, phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation and (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is to determine the NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine patients have been treated: 3 HNSCC, 4 lung, 2 liver. Overall tumor regression was observed in 8/9 patients of which 7 were anti-PD-1 non-responders. A complete response lasting over 1 year was observed in the injected lymph node in 1 anti-PD-1 naïve patient. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC patient and considered DLTs. This patient also experienced 2 other G4 SAEs related to anti-PD-1 (diabetic ketoacidosis, acute kidney injury). SBRT-related safety profile was as expected. Updated safety and efficacy results with additional patients and longer follow-up will be presented.

Conclusion: Safety data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in patients with advanced cancers, show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in patients having progressed on prior anti-PD-1. These data support further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs.

The post 2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial first appeared on Nano Publications.

2021 – Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients

nano-pub — Mon, 06 Jun 2022 07:43:52 +0000

Authors

Christophe Le Tourneau, Valentin Calugaru, Zoltan Takacsi-Nagy, Xavier Liem, Zsuzsanna Papai, Jacek Fijuth, Victor Moreno, Jordi Giralt, Sébastien Salas, Gilles Poissonnet, Emiliano Calvo, Bernard Doger, Olivier Choussy, Xavier Mirabel, Samar Krhili, Katell Bernois, Nicolas Fakhry, Stéphanie Wong-Hee-Kam, Edith Borcoman, Caroline Hoffmann

Institut Curie, Saint-Cloud, France; Institut Curie, Paris, France; Center of Radiotherapy-National Institute of Oncology, Budapest, Hungary; Centre Oscar Lambret, Lille, France; State Health Center, Hungarian Defense Forces, Oncology Department, Budapest, Hungary; Provita Prolife, Tomaszów Mazowiecki, Poland; START Madrid-FJD, Fundación Jiménez Díaz Hospital, Madrid, Spain; Vall d’Hebron University Hospital, Barcelona, Spain; CEPCM Assistance Publique des Hôpitaux de Marseille, Aix-Marseille Université, Marseille, France; Antoine-Lacassagne Anticancer center, Nice, France; START Madrid-CIOCC, Madrid, Spain; Hospital Universitario Fundacion Jimenez Diaz – START Madrid, Madrid, Spain; Oncology, Oscar Lambret Center, Lille, France; Nanobiotix, Paris, France; Hôpital Timone, AP-HM, Marseille, France; INSERM Unit U932 Immunity and Cancer, Institut Curie, Paris, France

Summary

Background: The non-surgical standard of care (SOC) for the treatment of locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication to cisplatin. However elderly patients, and those with poor performance status, comorbidities, and/or intolerance, may not benefit from these SOC treatments and represent a high unmet need. New approaches are thus needed to improve clinical outcomes without adding toxicity. NBTXR3, a novel radioenhancer, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by radiotherapy (RT).NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. We present here the results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population.

Methods: Patients with stage III-IVA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST 1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the phase I dose expansion part. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 – 222.3). At a median time of 7.8 months after NBTXR3 injection, the ORR of the primary lesion was 83.9% and the CRR 67.7% in the evaluable population for efficacy (N = 31). Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusions: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial. Clinical trial information: NCT01946867.

The post 2021 – Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients first appeared on Nano Publications.

2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial

nano-pub — Mon, 06 Jun 2022 07:48:56 +0000

Authors

Summary

The post 2021 – NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With Advanced Cancers: A Phase I Trial first appeared on Nano Publications.

2021 – NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers: phase I trial

nano-pub — Mon, 06 Jun 2022 07:47:18 +0000

Authors

C. Shen1, J.M. Frakes2, J. Niu3, A.J. Rosenberg4, J. Weiss5, J.J. Caudell6, K. Jameson7, P. Said8, and T.Y. Seiwert9

1 – Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC,
2 – H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL,
3 – Banner MD Anderson Cancer Center, Gilbert, AZ,
4 – Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL,
5 – University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC,
6 – Moffitt Cancer Center, Tampa, FL,
7 – Nanobiotix Corp, Cambridge, MA,
8 – Nanobiotix, Paris, France,
9 – Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL

Summary

Introduction: Immune checkpoint inhibitors (ICIs) have improved treatment outcomes in a variety of cancers; however the majority of patients (pts) exhibit resistance. Emerging evidence suggests radiation therapy (RT) can enhance response to ICIs by producing an immunomodulatory effect. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases RT energy deposition inside tumor cells and subsequent tumor cell death, without adding toxicity to healthy tissues. Preclinical data demonstrate NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders or convert ICI non-responders to responders.

Materials and Methods: A multicenter, open-label, phase I trial [NCT03589339] evaluating NBTXR3/SBRT/anti-PD-1 (nivolumab or pembrolizumab) in 3 cohorts (1) Locoregional recurrent or recurrent and metastatic HNSCC amenable to HN re-irradiation, (2) lung or (3) liver metastases from any primary cancer eligible for anti-PD-1. Stereotactic body RT (SBRT) is delivered at tumor-site specific doses per standard practice. Primary objective is to determine the NBTXR3/SBRT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety, and feasibility of NBTXR3 injection.

Results: Nine pts have been treated, 3 HNSCC, 4 lung and 2 liver. HNSCC was the primary cancer in 2 pts in the lung and 1 pt in the liver cohort. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/SBRT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. One anti-PD-1 naïve HNSCC pt achieved a complete response lasting over a year in the injected lymph node. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs (G4 diabetic ketoacidosis, G4 acute kidney injury) related to anti-PD-1. SBRT-related safety profile was as expected.

Conclusions: Safety data from this first-in-human phase I trial evaluating NBTXR3/SBRT/anti-PD-1 in pts with advanced cancers show NBTXR3 intratumoral injection is feasible and well-tolerated in HNSCC, lung, and liver metastases. NBTXR3/SBRT/anti-PD-1 demonstrated promising signs of efficacy and led to tumor regression in pts having progressed on prior anti-PD-1. These data support further development of NBTXR3/SBRT in combination with anti-PD-1 as well as other ICIs.

The post 2021 – NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers: phase I trial first appeared on Nano Publications.

2021 – Phase I Study of Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients

nano-pub — Fri, 27 May 2022 09:42:50 +0000

Authors

C. Le Tourneau1, V. Calugaru2, Z. Takacsi-Nagy3, X. Liem4, Z. Papai5, J. Fijuth6, V. Moreno Garcia7, I. Brana Garcia8, S. Salas9, G. Poissonnet10, E. Calvo7, B. Doger7, O. Choussy11, X. Mirabel12, S. Krhili13, K. Bernois14, N. Fakhry15, S. Wong Hee Kam16, E. Borcoman13, and C. Hoffmann13

1 – Department of Medical Oncology, Institut Curie, Paris, France
2 – Department of Radiation Oncology, Institut Curie, Paris, France
3 – National Institute of Oncology, Budapest, Hungary
4 – Université Montreal, Montreal, QC, Canada
5 – Magyar Honvedseg Egeszsegugyi Kozpont, Budapest, Hungary
6 – Medical University of Lodz, Lodz, Poland
7 – START Madrid, Madrid, Spain
8 – Vall D’Hebron Institute of Oncology, Barcelona, Spain
9 – Assistance Publique Hopitaux de Marseille, Timone Hospital, Marseille, France
10 – Unicancer – Antoine Lacassagne Center, Nice, France
11 – Department of head and neck surgery, Institut Curie, Paris, France
12 – Centre Oscar Lambret, Lille, France
13 – Institut Curie, Paris, France
14 – Nanobiotix, Paris, France
15 – Hopital Timone

Summary

Purpose/Objective(s): Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve the patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected once intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. We present here current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population (ClinicalTrials.gov: NCT01946867).

Materials/Methods: Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks). A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7-89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3-222.3). In the evaluable population for efficacy (N = 31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. The recruitment is ongoing and updated efficacy and safety results will be presented.

Conclusion: NBTXR3 intratumoral administration followed by IMRT may represent an option in elderly in elderly patients or patients with multiple comorbidities with LA-HNSCC who have limited therapeutic options. NBTXR3 activated by RT showed promising anti-tumor efficacy, supporting further evaluation in a phase III randomized trial.

The post 2021 – Phase I Study of Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally Advanced HNSCC Patients first appeared on Nano Publications.

2021 – Long-term results from the phase II/III Act.In.Sarc trial evaluating NBTXR3 in locally advanced STS

nano-pub — Fri, 27 May 2022 09:21:57 +0000

Authors

S. Bonvalot, P. Rutkowski, J. Thariat, S. Carrère, A. Ducassou, M. Sunyach, P. Agoston, A. Hong, A. Mervoyer, M. Rastrelli, C. Le, P. échoux, V. Moreno, R. Li, B. Tiangco, Z. Papai

Summary

Purpose or Objective: NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment in patients with locally advanced soft tissue sarcoma (LA STS) compared to RT alone. Primary endpoint of pCR rate (16% vs 8%; p=0.044) and main secondary endpoint of R0 margin rate (16% vs 8%; p=0.042) were met (Bonvalot et al. Lancet Oncol. 2019) while no modification of the early RT-associated safety profile was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Materials and Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT (NCT02379845). Patients received either a single intratumoral injection of NBTXR3 (equivalent to 10% of tumor volume, at 53.3g/L), plus EBRT (arm A) or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. Here we report on safety of NBTXR3+RT which was evaluated as secondary endpoint. Data were recorded on the “all treated population” during at least a two-year follow-up. Important parameters related to HR-QoL including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

The post 2021 – Long-term results from the phase II/III Act.In.Sarc trial evaluating NBTXR3 in locally advanced STS first appeared on Nano Publications.

2021 – Long-term evaluation of the novel radioenhancer NBTXR3 plus radiotherapy in patients with locally advanced soft tissue sarcoma treated in the phase II/III Act.In.Sarc trial

nano-pub — Mon, 06 Jun 2022 07:49:49 +0000

Authors

Sylvie Bonvalot, Piotr Rutkowski, Juliette Thariat, Sebastien Carrère, Anne Ducassou, Sunyach Marie, Peter Agoston, Angela M. Hong, Augustin Mervoyer, Marco Rastrelli, Cecile Le Pechoux, Victor Moreno, Rubi Khaw Li, Béatrice Tiangco, Zsuzsanna Papai, Act.In.Sarc. investigators

Institut Gustave Roussy, Villejuif, France; Maria Sklodowska-Curie Institute-Oncology Center, Institute of Oncology, Warsaw, Poland; Centre François Baclesse, Caen, France; Montpellier Cancer Institute, Montpellier, France; Institut Claudius Regaud, Toulouse, France; Centre Leon Berad, Lyon, France; Országos Onkológiai Intézet, Budapest, Hungary; Chris O’Brien Lifehouse, Camperdown, Australia; Institut de Cancérologie de l’Ouest – René Gauducheau, Radiation Therapy Department, Saint-Herblain, France; Istituto Oncologico Veneto IRCCS, Padova, Italy; Gustave Roussy Cancer Campus, Villejuif, France; Hospital Fundación Jiménez Díaz, Madrid, Spain; St Luke’s Medical Center, Quezon City, Philippines; The Medical City Cancer Center, Pasay City, Philippines; State Health Center, Hungarian Defense Forces, Oncology Department, Budapest, Hungary

Summary

Background: NBTXR3, a novel radioenhancer activated by radiotherapy (RT) demonstrated superior efficacy, as preoperative treatment, in patients with locally advanced soft tissue sarcoma (LA STS), compared to RT alone. Primary endpoint of pCR rate was 16% vs 8% (p=0.044) and R0 margin rate was 77% vs 64% (p=0.042) (Bonvalot et al. Lancet Oncol. 2019). No modification of the early safety profile of RT was observed, leading to market authorization. Here we report on the long-term safety, limb function and quality of life.

Methods: This phase II/III randomized (1:1), international trial included adult patients with LA STS of the extremity or trunk wall, requiring preoperative RT (NCT02379845). Patients were treated with either a single intratumoral injection of NBTXR3 (volume equivalent to 10% of tumor volume, at 53.3g/L) plus EBRT (arm A), or EBRT alone (arm B) (50 Gy in 25 fractions), followed by surgery. The primary and main secondary efficacy endpoints were previously reported. Safety of NBTXR3+RT, as preoperative treatment, was evaluated as secondary endpoint. We present the safety analyses done in the “all treated population”, with data recorded during at least a two-year follow-up. Important parameters related to HR-QoL, including functional outcome were studied using the EQ-5D, RNLI, TESS and MSTS questionnaires.

Results: Patients had at least two-year follow-up and the lost to follow-up rate was very low (1.9%). RT-related SAEs were observed in 11.2% (10/89) vs 13.3% (12/90) in A vs B. Post-treatment AEs, any grade, were observed in 51.7% (46/89) vs 57.8% (52/90) and serious post-treatment AEs in 13.5% (12/89) vs 24.4% (22/90) of patients in A vs B. Second primary cancer was observed in 1 patient in arm A and 6 patients in arm B. Long-term safety continues to demonstrate that NBTXR3 plus RT has no impact on post-surgical wound complications (24.7% vs 36.7%, A vs B). Furthermore, the evaluation of radiation late toxicities in limbs such as fibrosis (4.5% vs 7.7%), arthrosis (2.2% vs 0.0%) and edema (6.7% vs 2.2%) that may alter limb function showed no difference between arms. Accordingly, HR-QoL evaluation yielded no difference in functional outcome. In addition, the intratumoral injection of NBTXR3 did not induce cancer cell seeding at the former tumor site. Finally, sequelae or chronic tissue disturbances at the former tumor localization were similar in both treatment arms, confirming that the increase of energy dose deposit and the physical presence of NBTXR3 did not impact post-treatment limb functions.

Conclusions: The long-term safety results demonstrate that the addition of NBTXR3 to EBRT neither added toxicity nor modified the bystander effect of RT. The results presented here associated with the efficacy data reported previously reinforce the favorable benefit-risk ratio of the use of NBTXR3 in patients with LA STS. Clinical trial information: NCT02379845.

The post 2021 – Long-term evaluation of the novel radioenhancer NBTXR3 plus radiotherapy in patients with locally advanced soft tissue sarcoma treated in the phase II/III Act.In.Sarc trial first appeared on Nano Publications.

2021 – NBTXR3 activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients

nano-pub — Fri, 27 May 2022 09:17:02 +0000

Authors

C. Le Tourneau, V. Calugaru, Z. Takacsi-Nagy, X. Liem, Z. Papai, V. Moreno, I. Braña, S. Salas, G. Poissonnet, E. Calvo, B. Doger, O. Choussy, X. Mirabel, S. Krhili, K. Bernois, N. Fakhry, S. Wong Hee Kam, E. Borcoman, C. Hoffmann

Summary

Purpose or Objective: Concurrent radiotherapy (RT) with high-dose cisplatin, or cetuximab in case of intolerance to cisplatin, are the non-surgical standard treatment for locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, elderly patients, patients with poor performance status, comorbidities, and/or intolerance may not benefit from these treatments and represent a high unmet medical need. New approaches are thus needed to improve patient clinical outcomes without adding toxicity. NBTXR3, composed of functionalized hafnium oxide nanoparticles, is injected intratumorally and activated by RT. NBTXR3 increases the RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, without adding toxicity to healthy tissues. Here we present current results of the dose expansion part of the phase I study evaluating NBTXR3 plus intensity modulated radiation therapy (IMRT) in this population.

Materials and Methods: Patients with stage III-VA or T3/T4 (AJCC/UICC TNM staging system 8th ed.) HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab and amenable for RT, received a single intratumoral injection of NBTXR3 and IMRT (70 Gy in 35 fractions /7 weeks) [ NCT01946867]. A classical 3 + 3 dose escalation design has tested four doses of NBTXR3, equivalent to 5, 10, 15, and 22% of baseline theoretical tumor volume. The RP2D established as 22% of baseline tumor volume is further tested in the dose expansion part of the study. The primary endpoints of the dose expansion part are objective response rate (ORR) and complete response rate (CRR) of the primary tumor, by imaging according to RECIST v1.1. Safety is also evaluated.

Results: As of August 13, 2020, 43 patients have been treated in the dose expansion part of the study. The median age was 70.7 years old (range: 50.7- 89.9), 70% of patients had cardiac disorder risk, 44% had gastrointestinal disorder risk and 44% metabolic and nutrition disorder risk. The median tumor volume was 42.8 mL (range: 1.3 – 222.3). In the evaluable population for efficacy (N=31), the ORR of the primary lesion was 83.9% and the CRR 67.7% at a median time of 7.8 months after NBTXR3 injection. Three patients (7%) experienced at least one serious adverse event (AE) related to the injection procedure and/or NBTXR3 which represented less than 1% of all reported AEs. RT-related toxicity was as expected with IMRT. Three deaths due to AEs related to RT and other causes were reported. Recruitment is ongoing and updated efficacy and safety results will be presented.

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