A phase I/II trial of NBTXR3 nanoparticles activated by SBRT in the treatment of liver cancers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS551-TPS551 ◽  
Author(s):  
Enrique Chajon ◽  
Marc Pracht ◽  
Thierry De Baere ◽  
France Nguyen ◽  
Jean-Pierre Bronowicki ◽  
...  
Keyword(s):  
Adverse Event ◽  
Portal Vein ◽  
Phase I ◽  
Hafnium Oxide ◽  
Local Treatment ◽  
Complete Response ◽  
High Electron ◽  
Portal Vein Thrombus ◽  
Primary Endpoints ◽  
Liver Cancers

TPS551 Background: A new class of material with high electron density, hafnium oxide, was designed at the nanoscale (NBTXR3) to efficiently enhance the energy dose deposit from within the tumor cells and increase lethality of tumors, when exposed to radiotherapy (RT). The physical mode of action of NBTXR3 may represent a breakthrough approach for the local treatment of liver cancers, as it does not engage liver and renal functions, i.e. nanoparticles are not metabolized and not excreted by kidney. A phase I/II trial has been implemented for the treatment of hepatocellular carcinoma and liver metastasis [NCT02721056]. The study is currently recruiting patients. Methods: Patients (pts) receive a single intralesional (IL) injection of NBTXR3 (53.3g/L) at Volume levels equivalent to 10%, 15%, 22% and 33% of the baseline tumor volume, followed by RT (SBRT, 45Gy / 3 fractions / 5 to 7 days). For the Phase I part, primary endpoints include determination of the Recommended Dose and Dose Limiting Toxicities (DLT). The Phase II part will test three different groups of patients, HCC with portal vein thrombus, HCC without portal vein thrombus and a third cohort with liver metastases. Primary endpoints are complete response rate and safety. Results: Enrollment was completed for Volume levels 10% (6 pts) and 15% (4 pts) and is currently recruiting patients at 22% level. The NBTXR3 injections were successful in all cases. Radiotherapy has been delivered as planned without any DLT occurrence. No serious adverse event (SAE) related to NBTXR3 or the treatment procedure occurred. Three adverse events related to the injection were reported and no adverse event related to NBTXR3. Importantly, NBTXR3 nanoparticles did not have any impact on the reliability of image-guided radiation therapy (IGRT). Conclusion: The injection of NBTXR3 was safe and well tolerated at these levels. Patients received the planned RT. No DLT occurred. Enrollment is now opened at the 22% level. NBTXR3 shows promising results in terms of safety and antitumor activity and is also currently evaluated in other six clinical studies. Clinical trial information: NCT02721056.

A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6080-6080 ◽  
Author(s):  
Christophe Le Tourneau ◽  
Valentin Calugaru ◽  
Thomas Jouffroy ◽  
Jose Rodriguez ◽  
Caroline Hoffmann ◽  
...  
Keyword(s):  
Hafnium Oxide ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Treatment ◽  
Intensity Modulated Radiation Therapy ◽  
Complete Response ◽  
Injection Pain ◽  
High Electron ◽  
Recist 1.1 ◽  
Dose Levels

6080 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. Clinical trial information: NCT01946867.

scholarly journals OC-0281 Phase I/II trial of hafnium oxide nanoparticles activated by SBRT in the treatment of liver cancers

2019 ◽  
Vol 133 ◽  
pp. S139
Author(s):  
E. Chajon ◽  
M. Pracht ◽  
T. De Baere ◽  
F. N’Guyen ◽  
J. Bronowicki ◽  
...  
Keyword(s):  
Phase I ◽  
Hafnium Oxide ◽  
Oxide Nanoparticles ◽  
Liver Cancers

Hafnium oxide nanoparticles NBTXR3 activated by radiotherapy as a new therapeutic option for elderly/frail HNSCC patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6069-6069 ◽  
Author(s):  
Christophe Le Tourneau ◽  
Victor Moreno ◽  
Sebastien Salas ◽  
Xavier Mirabel ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Hafnium Oxide ◽  
Therapeutic Option ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Complete Response ◽  
Oxide Nanoparticles ◽  
Tumor Cell Death ◽  
Expansion Phase

6069 Background: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care treatment. NBTXR3, a crystalline solution of hafnium oxide nanoparticles may represent such an option. Injected intratumorally, NBTXR3 enters tumor cells and yields an increased cell-localized energy deposit upon exposure to radiotherapy (RT), leading to increased tumor cell death compared to the same dose of RT alone. Methods: Phase I study of NBTXR3 activated by RT in pts ≥70 years old or ≥65 years old and unable to receive cisplatin, eligible for exclusive RT with stage III or IV HNSCC of the oral cavity or oropharynx [NCT01946867]. A 3+3 dose escalation design was implemented with dose levels corresponding to 5%, 10%, 15% and 22% of baseline tumor volume, followed by an expansion phase. Pts received an intratumoral (IT) injection of NBTXR3 and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks). Determination of Recommended Phase 2 Dose (RP2D) and Dose Limiting Toxicities (DLT) were primary endpoints of phase I. Absence of NBTXR3 leakage and preliminary efficacy using RECIST 1.1 principles were also evaluated. Results: The dose-escalation is complete. Nineteen pts were enrolled: 3 at 5%, 3 at 10%; 5 at 15% and 8 at 22% with no observed DLT or SAE related to NBTXR3 or IT injection. One grade 1 NBTXR3-related AE (asthenia at 22%) and four IT injection-related AE (grade 2 oral pain; grade 1 tumor hemorrhage; grade 1 asthenia, and grade 1 injection site hemorrhage) were reported. RT-related toxicity was as expected with IMRT. RP2D has been determined to be 22%. CT-scan assessment between 24h and 7 weeks post-IT injection demonstrated absence of NBTXR3 leakage in the surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion. Conclusions: These results show that NBTXR3 activated by RT is safe and well tolerated at all doses with preliminary encouraging efficacy results. It thus represents a promising future treatment for frail and elderly pts with locally advanced HNSCC with limited therapeutic options. Expansion phase has started at the RP2D. Clinical trial information: NCT01946867.

Phase I trial of hafnium oxide nanoparticles activated by radiotherapy in cisplatin-ineligible locally advanced HNSCC patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6573-6573
Author(s):  
Christophe Le Tourneau ◽  
Valentin Calugaru ◽  
Edith Borcoman ◽  
Victor Moreno ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Hafnium Oxide ◽  
Locally Advanced ◽  
Complete Response ◽  
Oxide Nanoparticles ◽  
High Dose ◽  
Expansion Cohort ◽  
Anti Tumor Activity

6573 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 II 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. Conclusions: 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. Clinical trial information: NCT01946867 .

Radiation enhancing hafnium oxide nanoparticles (NBTXR3) for the treatment of cisplatin-ineligible locally advanced HNSCC patients: a phase I dose expansion study

Oral Oncology ◽  
2021 ◽  
Vol 118 ◽  
pp. 11
Author(s):  
Christophe Le Tourneau ◽  
Valentin Calugaru ◽  
Victor Moreno ◽  
Emiliano Calvo ◽  
Xavier Liem ◽  
...  
Keyword(s):  
Phase I ◽  
Hafnium Oxide ◽  
Locally Advanced ◽  
Oxide Nanoparticles

scholarly journals Distinguishing Tumor From Bland Portal Vein Thrombus in Liver Transplant Candidates With Hepatocellular Carcinoma: the A‐VENA Criteria

2019 ◽  
Vol 25 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Courtney B. Sherman ◽  
Spencer Behr ◽  
Jennifer L. Dodge ◽  
John P. Roberts ◽  
Francis Y. Yao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Portal Vein ◽  
Liver Transplant ◽  
Portal Vein Thrombus ◽  
Transplant Candidates

Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma

2008 ◽  
Vol 26 (36) ◽  
pp. 5950-5956 ◽  
Author(s):  
Jeffrey S. Weber ◽  
Steven O’Day ◽  
Walter Urba ◽  
John Powderly ◽  
Geoff Nichol ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Complete Response ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Multiple Doses ◽  
Group A ◽  
Group B

PurposeThe primary objective of this phase I/II study was to determine the safety and pharmacokinetic profile of either transfectoma- or a hybridoma-derived ipilimumab. Secondary objectives included determination of a maximum-tolerated dose and assessment of clinical activity.Patients and MethodsEighty-eight patients with unresectable stage III or IV melanoma with at least one measurable lesion were treated. Mean age was 59 years, with 65% male and 35% female patients, and 79% of patients had received prior systemic therapy. Single doses of ipilimumab up to 20 mg/kg (group A, single dose), multiple doses up to 5 mg/kg (group A, multiple dose), and multiple doses up to 10 mg/kg (group B) were administered.ResultsSingle dosing up to 20 mg/kg of transfectoma antibody was well tolerated, as were multiple doses up to 10 mg/kg without a maximum-tolerated dose. In group B, dose-limiting toxicity was seen in six of 23 melanoma patients. Grade 3 or 4 immune-related adverse events (irAEs) were observed in 14% of patients (12 of 88 patients), and grade 1 or 2 irAEs were seen in an additional 58%. The half-life of ipilimumab was 359 hours. In group B, there was one partial response (23+ months), one complete response (21+ months), and seven patients with stable disease (SD), for a disease control rate of 39%. Two patients in group B with SD had slow, steady decline in tumor burden that was ongoing at 1 year of observation.ConclusionIpilimumab has activity in patients with metastatic melanoma. Late responses were observed in patients with prolonged SD.

scholarly journals A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy

Blood ◽  
1993 ◽  
Vol 82 (9) ◽  
pp. 2624-2633 ◽  
Author(s):  
PL Amlot ◽  
MJ Stone ◽  
D Cunningham ◽  
J Fay ◽  
J Newman ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Dose Escalation Study ◽  
Ricin A Chain ◽  
A Chain ◽  
Reduced Toxicity ◽  
Mild Toxicity ◽  
Ricin A

Abstract Twenty-six patients, whose B-cell lymphoma had relapsed after conventional therapies, were treated in a phase I dose escalation study with an immunotoxin consisting of a mouse CD22 monoclonal antibody (RFB4:IgG1K) coupled to chemically deglycosylated ricin A chain (dgA). Two to 12 doses of the immunotoxin were infused intravenously at 48- hour intervals. The peak serum concentration and half-life (T1/2) did not correlate directly with the dose and averaged 3.8 micrograms/mL and 7.8 hours, respectively. The main dose-limiting toxicity was caused by the vascular leak syndrome (VLS) consisting of weight gain, edema, serum albumin decrease, and critically by pulmonary edema. Myalgia occurred frequently and was only dose limiting in one patient who developed rhabdomyolysis. The presence of lymphoma cells in the blood (> or = 10(10)/L) and clinically detectable splenomegaly were associated with reduced toxicity and a shorter T1/2. Nine of 24 evaluable patients (37.5%) made antibody to either mouse Ig or dgA. There were five partial responses (PR) and one complete response (CR) lasting 30 to 78 days. High peak concentrations of immunotoxin in the serum, a long T1/2, and large areas under the curve (AUC) correlated with both clinical response and toxicity. None of three patients with CD5+ lymphomas (including two CLL patients) had more than mild toxicity or responded to the immunotoxin.

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