Targeted Delivery of Chemotherapy With Ultrasound and Microbublles (SONCHIMIO)

• ClinicalTrials.gov Identifier: NCT03458975
• Recruitment Status: Recruiting
• First Posted: March 8, 2018
• Last Update Posted: April 8, 2020
• Sponsor: University Hospital, Tours
• Information provided by (Responsible Party): University Hospital, Tours

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer; Hepatic Metastases	Radiation: MRI; Radiation: Perfusion CT scan; Other: Contrast enhanced ultrasound; Drug: Sonoporation	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Targeted Delivery of Chemotherapy With Ultrasound and Microbubbles
• Actual Study Start Date: October 1, 2019
• Estimated Primary Completion Date: January 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Objective response for liver metastases [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Ayache Bouakaz, MD; +332 47 36 61 42; ayache.bouakaz@univ-tours.fr

Contact: Catherine Roussel; +33247479789; roussel@med.univ-tours.fr

Locations

France

Service d'Hépatogastro-entérologie CHRU de TOURS; Recruiting

Tours, France, 37044

Contact: LECOMTE Thierry, Pr +33 2 47 47 59 00 thierry.lecomte@univ-tours.fr

Contact: ROUSSEL Catherine, Mme +33 2 47 47 97 89 roussel@med.univ-tours.fr

Principal Investigator: LECOMTE Thierry, Pr

Sponsors and Collaborators

University Hospital, Tours

More Information

• Responsible Party: University Hospital, Tours
• ClinicalTrials.gov Identifier: NCT03458975
• Other Study ID Numbers: PRTK15-TL/SONCHIMIO
• First Posted: March 8, 2018
• Last Update Posted: April 8, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Tours:

microbubbles; sonoporation; hepatic metastases of colorectal cancer

Additional relevant MeSH terms:

Colorectal Neoplasms; Neoplasm Metastasis; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes