Targeted Delivery of Chemotherapy With Ultrasound and Microbublles
- Conditions
- Colorectal CancerHepatic Metastases
- Interventions
- Radiation: MRIRadiation: Perfusion CT scanOther: Contrast enhanced ultrasoundDrug: Sonoporation
- Registration Number
- NCT03458975
- Lead Sponsor
- University Hospital, Tours
- Brief Summary
The oscillations of ultrasound (US) contrast agent microbubbles under their activation by US waves engender a modulation of the permeability of biological barriers amplifying hence the extravasation of drugs and/or fluorescent markers through a process known as sonoporation. In such a way, the bioavailability of the therapeutic agent is augmented only in the area where US waves are focused. The objective now is to translate this therapeutic approach to the clinic by performing a feasibility study with the development of a therapy regime optimized for hepatic metastases of colorectal cancer.
In order to demonstrate the clinical feasibility of the therapeutic approach based on ultrasound and microbubbles, we will focus on patients with liver metastases of colorectal cancer treated with monoclonal antibodies in combination with chemotherapy.
- Detailed Description
Despite the increasing number of active molecules and the availability of news targeted therapies for cancer, therapeutic achievements remain modest for a number of tumor types. One of the major obstacles is inherent to the absence of specific delivery in the tumor tissue.
We have demonstrated recently that the oscillations of ultrasound (US) contrast agent microbubbles under their activation by US waves engender a modulation of the permeability of biological barriers amplifying hence the extravasation of drugs and/or fluorescent markers through a process known as sonoporation. In such a way, the bioavailability of the therapeutic agent is augmented only in the area where US waves are focused. The objective now is to translate this therapeutic approach to the clinic by performing a feasibility study with the development of a therapy regime optimized for hepatic metastases of colorectal cancer.
In order to demonstrate the clinical feasibility of the therapeutic approach based on ultrasound and microbubbles, we will focus on patients with liver metastases of colorectal cancer treated with monoclonal antibodies in combination with chemotherapy.
The work aims into evaluating the therapeutic efficacy of the proposed approach on a number of selected patients. We will follow the usual treatment schemes and we will apply imaging protocols to visualize tumor progression.
This technique of optimization of the intratumoral availability of anticancer drugs and based on sonoporation will improve the efficacy and safety of systemic chemotherapy by providing increased tumor uptake relative to normal tissue. This technique provides an ideal and easy strategy to optimize intratumoral drug delivery.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 7
- patient with liver metastases from colorectal cancer; patient with minimum two liver metastases which satisfy all the following criteria: diameter between 10 and 35 mm; arterially enhancing liver metastases detected with contrast enhanced ultrasound (CEUS); measurable liver metastases with CT-scan (Acceptability of a patient with more than 4 metastases or a patient with an odd number of metastases ≥ 2).
- age ≥ 18 years;
- ECOG/OMS 0-1;
- life expectancy of at least 12 weeks;
- adequate bone marrow, liver and kidney function;
- written informed consent obtained from subject;
- subjects covered by or having the rights to social security;
- bi-weekly chemotherapy regimen
- neo-adjuvant standard chemotherapy or palliative standard chemotherapy (first or second metastatic line) following the recommendations in force (national thesaurus of digestive oncology - colorectal cancer chapter: Phelip JM, Benhaim L, Bouché O, Christou N, Desolneux G, Dupré A, Léonard D, Michel P, Penna C, Rousseaux B, Tougeron D, Tournigand C. "Cancer colorectal métastatique". Thésaurus National de Cancérologie Digestive, Janvier 2019, http://www.tncd.org).
- Previous local treatment of selected liver metastases (radiofrequency, radioembolization, ...);
- Indication for local ablative therapy of selected liver metastasis (radiofrequency ablation or other validated hepatic-directed modality of treatment);
- Previous malignancy other than colorectal adenocarcinoma within 3 years prior to the inclusion with the exception for curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer;
- Known contraindication to the injection of Sonovue®, of Gadolinium, of iodated contrast agent;
- contraindication to MRI or perfusion CT scan;
- Patient under legal protection;
- Pregnant or lactating woman, or woman with ability to procreate and without contraception;
- Inclusion in another therapeutic trial
- Uracilemia greater than or equal to 150ng/mL (suggestive of a complete DPD deficiency).
- Presence of any material with potential interaction with ultrasound beam (metal, etc.) or healing tissue, and which cannot be bypassed
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Selected liver metastases of the patient MRI Liver metastases randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy Selected liver metastases of the patient Perfusion CT scan Liver metastases randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy Selected liver metastases of the patient Contrast enhanced ultrasound Liver metastases randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy Selected liver metastases of the patient Sonoporation Liver metastases randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy Not-selected liver metastases of the patient MRI Liver metatstases not randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy like the active comparator arm Not-selected liver metastases of the patient Perfusion CT scan Liver metatstases not randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy like the active comparator arm Not-selected liver metastases of the patient Contrast enhanced ultrasound Liver metatstases not randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy like the active comparator arm
- Primary Outcome Measures
Name Time Method Objective response for liver metastases 2 months Objective response for liver metastases with spiral CT scan and defined as decrease of at least 30% in the longer diameter of each selected liver metastases
- Secondary Outcome Measures
Name Time Method Safety Day 3, Day 17, Day 32, Day 47 Safety based on National Cancer Institute (NCI), Common Terminology Criteria for Adverse events (CTCAE)
Tolerance Day 3, Day 17, Day 32, Day 47 Tolerance based on National Cancer Institute (NCI), Common Terminology Criteria for Adverse events (CTCAE)
Maximum percent reduction in tumor density on CT scan 2 months Maximum percent reduction in tumor density (Hounsfield units) from baseline
Maximum percent reduction in tumor density on MRI 2 months Maximum percent reduction in tumor density from baseline
Assessment of tumor vascularity by MRI 2 months Assessment of tumor vascularity with MRI
Assessment of tumor vascularity by Dynamic Contrast-Enhanced US (DCE-US) 2 months Assessment of tumor vascularity with Dynamic Contrast-Enhanced US (DCE-US)
Assessment of tumor vascularity by Perfusion CT scan 2 months Assessment of tumor vascularity with Perfusion CT scan
Dosage of antibody anti-VEGF or anti-EGFR Day1, Day 3, Day 15, Day 17, Day 32, Day 45 Measures of serum concentration of antibody anti-VEGF or anti-EGFR
Dosage of antibody anti-VEGF or anti-EGFR by ELISA test Day1, Day 3, Day 15, Day 17, Day 32, Day 45 Pharmacokinetic of antibody anti-VEGF or anti-EGFR
Dosage of cytokines Day1, Day 3, Day 15, Day 17, Day 32, Day 45 Dosage of cytokines
Trial Locations
- Locations (1)
Service d'Hépatogastro-entérologie CHRU de TOURS
🇫🇷Tours, France