Nanoparticle-Enhanced Radiotherapy for Pancreatic Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Dana-Farber Cancer Institute
Must be taking: Induction chemotherapy
Must not be taking: Antiretrovirals
Disqualifiers: Metastatic disease, Prior radiation, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This research study is being done to help determine the safety and efficacy of gadolinium based nanoparticle, Activation and Guidance of Irradiation X (AGuIX), used in conjunction with MR-guided stereotactic body radiation therapy (SBRT) in the treatment of pancreatic cancer and lung tumors.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on combination antiretroviral therapy for HIV, you would be ineligible due to potential interactions with the study drug.
What data supports the effectiveness of the treatment AGuIX for pancreatic cancer?
AGuIX nanoparticles have shown promise in enhancing the effects of radiation therapy by making cancer cells more sensitive to radiation, as seen in studies with pancreatic cancer cells and other cancer types like brain and lung. These nanoparticles accumulate in tumors and help improve the effectiveness of radiation treatment, potentially leading to better outcomes.
12345Is the nanoparticle-enhanced radiotherapy treatment AGuIX safe for humans?
AGuIX nanoparticles have been tested in animals (rodents and monkeys) with no evidence of toxicity, and early human trials have shown no observed toxicity, suggesting they are generally safe for use in humans.
23467What makes the treatment AGuIX unique for pancreatic cancer?
AGuIX is unique because it uses gadolinium-based nanoparticles to enhance the effects of radiation therapy by making cancer cells more sensitive to radiation, while also allowing for better imaging of the tumor. This dual function helps target the cancer more precisely and potentially reduces damage to healthy tissues.
12358Eligibility Criteria
This trial is for adults with certain types of lung or pancreatic cancer that can't be removed by surgery. Participants must have completed standard chemotherapy if they have pancreatic cancer, and their tumors should be no larger than 5cm. They need to have normal organ function, no distant metastasis, and an ECOG performance status ≤2 (which means they are able to walk and do some activities).Inclusion Criteria
You must have a visible and measurable disease that can be accurately measured.
I can take care of myself but might not be able to do heavy physical work.
My lung cancer has not spread to my lymph nodes and cannot be removed by surgery.
+11 more
Exclusion Criteria
Participants who are receiving any other investigational agents
You have had allergic reactions to a specific type of contrast dye used for imaging tests.
My cancer has spread to other parts of my body.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive AGuIX nanoparticles and stereotactic body radiation therapy (SBRT) over 5 treatment days
2 weeks
5 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
Regular follow-up visits
Extension
Participants may continue to be monitored for long-term outcomes such as overall survival and quality of life
Up to 100 months
Participant Groups
The study tests a new treatment combining AGuIX nanoparticles with MR-guided stereotactic body radiation therapy (SBRT) for treating non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma. The goal is to see how safe this combination is and how well it works against these cancers.
3Treatment groups
Experimental Treatment
Group I: SMART Phase 2Experimental Treatment1 Intervention
Randomized participants will receive standard of care SMART, magnetic resonance imaging (MR)-guided stereotactic body radiation therapy (SBRT).
Group II: AGUIX + SMART Phase 2Experimental Treatment2 Interventions
Randomized participants will receive recommended phase 1 dose established for their disease group (central lung tumor or locally advanced/unresectable pancreatic ductal adenocarcinoma-LAPC) of Activation and Guidance of Irradiation X (AGUIX) and SMART, magnetic resonance imaging (MR)-guided stereotactic body radiation therapy (SBRT).
Group III: AGUIX + SMART Phase 1Experimental Treatment2 Interventions
Dose escalation of Activation and Guidance of Irradiation X (AGUIX) and SMART, magnetic resonance imaging (MR)-guided stereotactic body radiation therapy (SBRT).
Central lung tumor cohort will receive:
* five fractions of stereotactic body radiation therapy (SBRT)
* AGuIX Nanoparticle given on -7 or -14 day prior to radiation treatment, then with 1st fraction of radiation and for patients receiving radiation over a two (2) week period with the 4th fraction of radiation .
Locally advanced/unresectable pancreatic ductal adenocarcinoma-LAPC cohort, will receive:
five fractions of stereotactic body radiation therapy (SBRT)
* AGuIX Nanoparticle given on -7 or -14 day prior to radiation treatment, then with 1st fraction of radiation.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dana Farber Cancer InstituteBoston, MA
Brigham & Women's HospitalBoston, MA
Brigham and Women's HospitalBoston, MA
Loading ...
Who Is Running the Clinical Trial?
Dana-Farber Cancer InstituteLead Sponsor
NH TherAguix SASCollaborator
References
AGuIX nanoparticles as a promising platform for image-guided radiation therapy. [2020]AGuIX are gadolinium-based nanoparticles developed mainly for imaging due to their MR contrast properties. They also have a potential role in radiation therapy as a radiosensitizer. We used MRI to quantify the uptake of AGuIX in pancreatic cancer cells, and TEM for intracellular localization. We measured the radiosensitization of a pancreatic cancer cell line in a low-energy (220 kVp) beam, a standard 6 MV beam (STD) and a flattening filter free 6 MV beam (FFF). We demonstrated that the presence of nanoparticles significantly decreases cell survival when combined with an X-ray beam with a large proportion of low-energy photons (close to the k-edge of the nanoparticles). The concentration of nanoparticles in the cell achieves its highest level after 15 min and then reaches a plateau. The accumulated nanoparticles are mainly localized in the cytoplasm, inside vesicles. We found that the 6 MV FFF beams offer the best trade-off between penetration depth and proportion of low-energy photons. At 10 cm depth, we measured a DEF20 % of 1.30 ± 0.47 for the 6 MV FFF beam, compared to 1.23 ± 0.26 for the 6 MV STD beam. Additional measurements with un-incubated nanoparticles provide evidence that chemical processes might also be contributing to the dose enhancement effect.
AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine. [2021]AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.
Evaluation of Novel 64Cu-Labeled Theranostic Gadolinium-Based Nanoprobes in HepG2 Tumor-Bearing Nude Mice. [2020]Radiation therapy of liver cancer is limited by low tolerance of the liver to radiation. Radiosensitizers can effectively reduce the required radiation dose. AGuIX nanoparticles are small, multifunctional gadolinium-based nanoparticles that can carry radioisotopes or fluorescent markers for single-photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, and even multimodality imaging. In addition, due to the high atomic number of gadolinium, it can also serve as a tumor radiation sensitizer. It is critical to define the biodistribution and pharmacokinetics of these gadolinium-based nanoparticles to quantitate the magnitude and duration of their retention within the tumor microenvironment during radiotherapy. Therefore, in this study, we successfully labeled AGuIX with 64Cu through the convenient built-in chelator. The biodistribution studies indicated that the radiotracer 64Cu-AGuIX accumulates to high levels in the HepG2 xenograft of nude mice, suggesting that it would be a potential theranostic nanoprobe for image-guided radiotherapy in HCC. We also used a transmission electron microscope to confirm AGuIX uptake in the HepG2 cells. In radiation therapy studies, a decrease in 18F-FDG uptake was observed in the xenografts of the nude mice irradiated with AGuIX, which was injected 1 h before. These results provide proof-of-concept that AGuIX can be used as a theranostic radiosensitizer for PET imaging to guide radiotherapy for liver cancer.
Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification. [2023]Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd3+ cations with higher Z Bi3+. These next-generation nanoparticles are based on the AGuIX® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX® is used as an initial chelation platform to exchange Gd3+ for Bi3+. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi3+. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.
MRI-guided clinical 6-MV radiosensitization of glioma using a unique gadolinium-based nanoparticles injection. [2017]This study reports the use of gadolinium-based AGuIX nanoparticles (NPs) as a theranostic tool for both image-guided radiation therapy and radiosensitization of brain tumors.
[Ultrasmall nanoparticles for radiotherapy: AGuIX]. [2015]Since twenty years, many nanoparticles based on high atomic number elements have been developed as radiosensitizers. The design of these nanoparticles is limited by the classical rules associated with the development of nanoparticles for oncology and by the specific ones associated to radiosensitizers, which aim to increase the effect of the dose in the tumor area and to spare the health tissues. For this application, systemic administration of nanodrugs is possible. This paper will discuss the development of AGuIX nanoparticles and will emphasize on this example the critical points for the development of a nanodrug for this application. AGuIX nanoparticles display hydrodynamic diameters of a few nanometers and are composed of polysiloxane and gadolinium chelates. This particle has been used in many preclinical studies and is evaluated for a further phase I clinical trial. Finally, in addition to its high radiosensitizing potential, AGuIX display MRI functionality and can be used as theranostic nanodrug for personalized medicine.
The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy. [2022]A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (
Advanced multimodal nanoparticles delay tumor progression with clinical radiation therapy. [2022]Radiation therapy is a major treatment regimen for more than 50% of cancer patients. The collateral damage induced on healthy tissues during radiation and the minimal therapeutic effect on the organ-of-interest (target) is a major clinical concern. Ultra-small, renal clearable, silica based gadolinium chelated nanoparticles (SiGdNP) provide simultaneous MR contrast and radiation dose enhancement. The high atomic number of gadolinium provides a large photoelectric cross-section for increased photon interaction, even for high-energy clinical radiation beams. Imaging and therapy functionality of SiGdNP were tested in cynomolgus monkeys and pancreatic tumor-bearing mice models, respectively. A significant improvement in tumor cell damage (double strand DNA breaks), growth suppression, and overall survival under clinical radiation therapy conditions were observed in a human pancreatic xenograft model. For the first time, safe systemic administration and systematic renal clearance was demonstrated in both tested species. These findings strongly support the translational potential of SiGdNP for MR-guided radiation therapy in cancer treatment.