Sonoporation and Tumor Microenvironment Response in Colorectal Liver Metastases

Official title

Tumor Response to Sonoporation: A Clinical Translational RCT of Contrast-enhanced Ultrasound Induced Changes in Tumor Microenvironment of Colorectal Liver Metastases

Overview

This study is an investigator-initiated, randomized controlled trial enrolling patients with colorectal liver metastases. The objectives are to evaluate the safety and efficacy of contrast-enhanced ultrasound (CEUS)-mediated sonoporation as a potential therapeutic intervention and to investigate whether sonoporation can modulate the tumor microenvironment toward a more immune-active state

Detailed description

The trial is designed as an investigator-initiated, multicenter, prospective, randomized, controlled, two-arm, intervention trial with a matched historical control group aims to evaluate the therapeutic potential of contrast-enhanced ultrasound (CEUS) in patients with colorectal liver metastases (CLM). The primary objectives are to assess whether CEUS can modulate the tumor microenvironment and to determine the safety, tolerability, and feasibility of CEUS as a therapeutic modality. Eligible patients will be randomized to receive either low-intensity CEUS (LI-CEUS) or high-intensity CEUS (HI-CEUS) focused on a designated study metastasis. Safety, feasibility, and success-rate of the intervention will be registered. Minimum seven days post-intervention a biopsy of the study metastasis will be conducted. Subsequent analyses will compare immune cell infiltration, immune-related gene expression, and stromal and vascular remodeling in LI-CEUS- and HI-CEUS-exposed metastases versus historical controls.

Interventions

• Other Low-intensity contrast enhanced ultrasound
  The LI-CEUS arm will receive a 30-minute contrast-enhanced ultrasound session targeting a designated study metastasis. During the procedure, 1 mL of the ultrasound contrast agent SonoVue will be administered every 3 minutes throughout the entire session. Minimum 7 days after the intervention a biopsy of the study metastasis will be conducted.
• Other High-intensity contrast enhanced ultrasound
  The HI-CEUS intervention group will recieve a 30-minute CEUS procedure targeting a designated study metastasis. During the procedure, 1 mL of the ultrasound contrast agent SonoVue will be administered every 3 minutes throughout the entire session. A high-intensity ultrasound "flash" will be applied every 30 seconds. This "flash" consists of a brief sequence of ultrasound waves with a high mechanical index that causes complete destruction of microbubbles within the imaging field. Minimum 7 days a

Primary outcome measures

• Immune cell density (CD8+, CD3+) in colorectal liver metastases exposed to LI-CEUS or HI-CEUS, compared to controls. [Time frame: ≥7 days after postinterventional]

Secondary outcome measures (5)

• Number of participants in the intervention group with treatment-related adverse events assessed by CTCAE v5.0 [Time frame: Daily, until 7 days post-interventional]
• Procedure success of LI-CEUS and HI-CEUS procedures as assessed by operator-defined completion of the planned intervention [Time frame: Periinterventional]
• Differential expression of immune-related genes between CEUS-exposed and control liver metastases [Time frame: ≥7 days postinterventional]
• Systemic immune response assessed by changes in the circulating cytokine profiles following LI-CEUS and HI-CEUS [Time frame: Pre- and ≥7 days postinterventional]
• Frequency and type of technical issues encountered during LI-CEUS and HI-CEUS procedures assessed by the operator [Time frame: Periinterventional]

Eligibility criteria

Inclusion criteria

• Adult patients (≥18 years)
• Ability to provide written informed consent
• Histopathological confirmed colorectal adenocarcinoma
• Scheduled for liver resection or ablation at the Rigshospital, or admitted to oncologic treatment due to colorectal liver metastases (CLM) at Zealand University Hospital
• Presence of at least one CLM evaluable and accessible by CEUS
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Follow the conditions regarding fertility, pregnancy, or lactation:

• Women of childbearing potential (WOCBP) are defined as women ranging from the period of menarche till the post-menopausal period, unless permanently sterile (e.g. hysterectomy, bilateral salpingectomy and bilateral oophorectomy), Post-menopause is defined as no menses for 12 months without an alternative medical cause.
• WOCBP should use a secure and highly effective birth control (as stated in the "Recommendations related to contraception and pregnancy testing in clinical trials", version 1.1, section 4.1, from the Clinical Trials Facilitation and Coordination Group) during the entire period of the trial. In cases of uncertainty regarding pregnancy, pregnancy testing either as highly sensitive serum or urine pregnancy test will be used.

Exclusion criteria

• Oncologic systemic treatment 2 weeks prior to inclusion
• Prior treatment with an immune checkpoint inhibitor (e.g. anti-PD-L1, anti PD-1, or anti-PD-L2)
• Inability to reliably distinguish the study metastasis from other hepatic metastases using CEUS
• Systemic treatment with either corticosteroids (>10 mg daily prednisolone equivalents) or other immunosuppressive medications within 2 weeks prior inclusion. Inhaled or topical steroids and adrenal replacements doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Known history of human immunodeficiency virus (HIV), active or chronic hepatitis B, or C.
• Pregnancy or lactation.
• Confirmed dMMR positive primary tumors
• Inability to comply with study protocol due to psychological, social, or logistical reasons.
• Contraindications for CEUS:

• Known hypersensitivity to SonoVue® or any other ultrasound contrast agent
• Uncontrolled atrial hypertension
• Known right-to-left intracardiac shunt
• Severe pulmonary hypertension (SAP >90 mmHg)
• Adult respiratory distress syndrome.
• Known hypersensitivity to macrogols
• Unstable ischemic heart disease or acute coronary syndrome
• Severe lung disease, e.g. severe chronic obstructive lung disease

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Denmark · 2 centers

• Rigshospitalet — Copenhagen
• Surgical Department, Zealand University Hospital — Køge

Identifiers

NCT: NCT07365527 · P-2025-19453

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗