Targeted Delivery of Chemotherapy With Ultrasound and Microbublles (SONCHIMIO)

Targeted Delivery of Chemotherapy With Ultrasound and Microbubbles

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Hepatic Metastases
• Intervention / Treatment: Radiation: MRI; Radiation: Perfusion CT scan; Other: Contrast enhanced ultrasound; Drug: Sonoporation

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Tours, France, 37044
    • Service d'Hépatogastro-entérologie CHRU de TOURS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Selected liver metastases of the patient; Liver metastases randomized to receive sonoporation (US waves + gaseous microbubbles). The patient continue to receive the usual systemic chemotherapy	Radiation: MRI; Magnetic Resonance Imaging; Radiation: Perfusion CT scan; Perfusion Computerized tomography scan; Other: Contrast enhanced ultrasound; Contrast enhanced ultrasound; Drug: Sonoporation; Gaseous microbubbles (Sonovue) combinated with Ultrasounds
Placebo Comparator: Not-selected liver metastases of the patient; 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	Radiation: MRI; Magnetic Resonance Imaging; Radiation: Perfusion CT scan; Perfusion Computerized tomography scan; Other: Contrast enhanced ultrasound; Contrast enhanced ultrasound

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response for liver metastases	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	2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Safety based on National Cancer Institute (NCI), Common Terminology Criteria for Adverse events (CTCAE)	Day 3, Day 17, Day 32, Day 47
Tolerance	Tolerance based on National Cancer Institute (NCI), Common Terminology Criteria for Adverse events (CTCAE)	Day 3, Day 17, Day 32, Day 47
Maximum percent reduction in tumor density on CT scan	Maximum percent reduction in tumor density (Hounsfield units) from baseline	2 months
Maximum percent reduction in tumor density on MRI	Maximum percent reduction in tumor density from baseline	2 months
Assessment of tumor vascularity by Perfusion CT scan	Assessment of tumor vascularity with Perfusion CT scan	2 months
Assessment of tumor vascularity by MRI	Assessment of tumor vascularity with MRI	2 months
Assessment of tumor vascularity by Dynamic Contrast-Enhanced US (DCE-US)	Assessment of tumor vascularity with Dynamic Contrast-Enhanced US (DCE-US)	2 months
Dosage of antibody anti-VEGF or anti-EGFR	Measures of serum concentration of antibody anti-VEGF or anti-EGFR	Day1, Day 3, Day 15, Day 17, Day 32, Day 45
Dosage of antibody anti-VEGF or anti-EGFR by ELISA test	Pharmacokinetic of antibody anti-VEGF or anti-EGFR	Day1, Day 3, Day 15, Day 17, Day 32, Day 45
Dosage of cytokines	Dosage of cytokines	Day1, Day 3, Day 15, Day 17, Day 32, Day 45

Collaborators and Investigators

• Sponsor: University Hospital, Tours

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: March 2, 2018
• First Submitted That Met QC Criteria: March 2, 2018
• First Posted (Actual): March 8, 2018

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 6, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: microbubbles; sonoporation; hepatic metastases of colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: PRTK15-TL/SONCHIMIO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No