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NCT Number: NCT07406126

Yttrium-90 Radioembolization Neoadjuvant Therapy With Immune Marker Profiling and Dosimetry for Potentially Resectable Patients With Colorectal Liver Metastases

This is a observational, prospective, single arm, proof of concept study to assess safety, feasibility, and potential efficacy of combining Yttrium-90 transarterial radioembolization(TARE) with standard systemic therapy in clinical practice for potentially resectable patients with colorectal liver metastases (CRLM). Alternatively, resectability will also be evaluated. The investigators hypothesize that by applying this approach, higher local control and resection rates can be achieved (typically below 13% for patients who are initially deemed unresectable). Additionally, this treatment option is expected to help delay or reduce the need for (a switch in) systemic treatment and eventually improve survival in patients with liver metastases that are not resectable. All studies reporting the results of TARE at ablative doses are retrospective cohort studies or cases series. Prospective data is needed to expand the indications and reimbursement of radioembolization.

Other objectives of the study are:

* To calculate the resection rate in patients undergoing the combined approach. * To evaluate immune markers in peripheral blood and resected metastases. * To formulate the first concept of an algorithm, enable to deliver personalized AI assisted dosimetry. * To assess potential role of circulating tumor DNA (ctDNA) in evaluation of patient prognosis and follow up. * To determine the grade of necrosis at the time of resection and correlate with the absorbed dose.

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Key information

Conditions

Colorectal Liver Metastases (CRCLM) Neoplasm Metastasis Neoplasms Neoplastic Processes Pathologic Processes Pathological Conditions, Signs and Symptoms Unresectable Colorectal Liver Metastases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Hospital Universitario de Navarra, Pamplona, Navarre, Spain

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Histologically confirmed primary adenocarcinoma of the colon or rectum
  • Potentially resectable colorectal liver metastases, with limiting factors for resection including:
  • Insufficient future liver remnant.
  • Unfavorable tumor location (e.g. involvement of a major vessel and/or bile duct)/ large size and/ or number of lesions, which limit resection with R0 margins and requires downsizing of the metastases
  • No or limited extrahepatic metastatic disease (limited extrahepatic disease should be amenable to eradicate with locoregional therapies as per multidisciplinary discussion of surgeons, radiation oncologists and interventional radiologists)
  • Patient should match standard 90Y radioembolization inclusion criteria:
  • Signed informed consent;
  • Age ≥ 18 years;
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
  • Life expectancy of ≥ 3 months;
  • Measurable target tumors in the liver according to RECIST 1.1
  • Laboratory parameters: eGFR >45/mL/min/1.73 m2; albumin > 3.0 g/dl, normal bilirubin (unless Gilbert syndrome); aminotransferase (ALAT/ASAT) <3.0 ULN

Exclusion criteria

  • Life expectancy ≤3 months
  • Patient initially eligible for surgery or thermal ablation of the liver metastases
  • Progressive extra-hepatic disease
  • Active extra-hepatic disease that cannot be treated
  • Life-threatening extra-hepatic disease (i.e. dialysis, unresolved diarrhea, serious unresolved infections (HIV, HBV, HCV etc.))
  • Uncorrectable coagulopathy
  • Contraindication for angiography or MRI
  • Significant toxicities due to prior cancer therapy that have not resolved before the initiation of the study; if the investigator determines that the continuing complication will compromise the safe treatment of the patient
  • Any surgical contraindication
  • Ascites
  • Expected difficulties for safe execution of TARE based on pretreatment Tc99m-MAA imaging, including;
  • Flow to extra-hepatic vessels not correctable by reposition of catheter or embolization Uncorrectable estimated dose to the lungs >30Gy in a single administration or >50Gy cumulatively
  • Uncorrectable estimated dose to the untreated liver of >70Gy
  • Estimated average dose to the viable tumor volume <200Gy
  • Prior liver radiotherapy
  • Severe portal hypertension
  • Second primary malignancy within the past 5 years, other that adequately treated non-melanoma skin cancer, carcinoma in situ of any organ or second primary colorectal cancer
  • Unresectable primary tumor in situ;
  • Other serious comorbidity or any other condition, that renders patients unsuitable for the study treatment
  • Pregnancy, lactation or refusal to use adequate contraceptive measures
  • History of allergic reaction to any components of the treatment that cannot be medically corrected.

Treatment and study plan

Yttrium-90 Radioembolization with standard systemic therapy

Procedure

Yttrium-90 microspheres are administered through the hepatic artery which supplies blood to tumor tissue (the portal vein supplies blood to the normal hepatic tissue). The microspheres are trapped in the vasculature of the tumor due to arteriolar capillary blockage where they exert a local radiotherapeutic effect. In clinical use, the glass microspheres remain permanently trapped in the vasculature where the isotope decays to infinity leaving background radiation with no therapeutic value. This procedure is combined with standard systemic therapy per routine clinical practice.

Primary outcomes

  1. Monitoring for adverse events related to the procedure.

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM. Safety assessments will include monitoring for adverse events related to the procedure.

  2. Evaluate the safety related to the procedure by measuring changes in Liver function values in blood.

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    To evaluate hepatic safety after neoadjuvant ablative-dose Yttrium-90 radioembolization combined with standard systemic therapy in patients with CRLM changes in laboratory biomarkers will be compared with baseline values and subsequent assessments.

    Biomarkers and Units of Measure:

    • Liver Function Markers: Bilirubin (mg/dL), Albumin (g/dL), Aspartate Aminotransferase (AST) (U/L), Alanine Aminotransferase (ALT) (U/L), Gamma-Glutamyl Transferase (GGT) (U/L), Alkaline Phosphatase (FA) (U/L), Cholinesterase (ChE) (U/L), Lactate Dehydrogenase (LDH) (U/L)

  3. Evaluate the safety related to the procedure by measuring changes in Liver function values in blood.

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    To evaluate hepatic safety after neoadjuvant ablative-dose Yttrium-90 radioembolization combined with standard systemic therapy in patients with CRLM changes in laboratory biomarkers will be compared with baseline values and subsequent assessments.

    Biomarkers and Units of Measure:

    Inflammatory Marker: C-reactive protein (CRP) (mg/L) Renal Function Marker: Creatinine (mg/dL)

  4. Evaluate the safety related to the procedure by measuring changes in Liver function values in blood.

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    To evaluate hepatic safety after neoadjuvant ablative-dose Yttrium-90 radioembolization combined with standard systemic therapy in patients with CRLM changes in laboratory biomarkers will be compared with baseline values and subsequent assessments.

    Biomarkers and Units of Measure:

    Composite Liver Function Scores: Albumin-Bilirubin (ALBI) score (unitless), Albumin-Bilirubin (ALBI) grade (ordinal scale)

  5. Evaluate the safety related to the procedure by measuring changes in tumor markers in blood.

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM by assessing tumor markers in blood: Carcinoembryonic antigen (CEA) and CA 19-9.

  6. Evaluate the quality of Life After Liver Resection Assessed by FACT-C (Version 4) Following 90Y Radioembolization

    Time frame: From 90Y radioembolization (week 2-4) to the end of study at 30 weeks

    Evaluate the safety of combining neoadjuvant ablative dose 90Y radioembolization with standard systemic therapy in patients with CRLM. Safety assessments will include assessing overall well-being of the patients focus on quality of life after liver resection.

    Outcome Measure: Change in Functional Assessment of Cancer Therapy-Colorectal (FACT-C, Version 4) total score from baseline to 30 weeks. The FACT-C (Version 4) total score and each subscale will be analyzed as independent measures to evaluate longitudinal changes in overall well-being and postoperative recovery after liver resection, characterizing treatment-related safety and tolerability.

    Quality-of-Life Instrument:

    Functional Assessment of Cancer Therapy-Colorectal (FACT-C, Version 4): Total score and subscale scores (Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Colorectal Cancer Subscale), reported according to standard scoring guidelines.

  7. Evaluate the efficacy of the procedure by tumor response rate assessed by means of RECIST 1.1

    Time frame: From week 0 to resection, progression or week 26-28

    Efficacy assessments will include tumor response rate assessed by means of RECIST 1.1. Baseline efficacy imaging scans will be conducted during the screening phase. Efficacy assessment scans will follow standard-of-care clinical management guidelines, occurring every 8 weeks (with a variance of +/- 1 week) post-inclusion until resection or until progression.

  8. Evaluate the efficacy of the procedure: pathologic response assessment on the resected specimens.

    Time frame: From week 0 to resection, progression or week 26-28

    Efficacy assessments will include tumor response rate assessed by means of RECIST 1.1. It will be of capital interest the pathologic response assessment on the resected specimens.

Secondary outcomes

  1. Resection rate in patients undergoing the combined approach

    Time frame: week 18-20 and week 26-28

    It will indicate the percentage of patients who ultimately proceed to surgical resection of their liver metastases after receiving TARE as part of the neoadjuvant therapy. The decision of resection will be taken in the respective multidisciplinary meetings of each participating center.

  2. Cellular population quantification on peripheral blood samples: leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

    Time frame: Week 0, 6, 8 and 16

    Microbial fuel cell procedure will be performed on peripheral blood samples within the first 24-36 hours after collection. Bulk lysis technique will be done with the aim to concentrate leukocytes and, later, to detect minority populations. The quantification of each population will be performed in percentage and in absolute count, estimating the cells per microliter from the leukocyte value obtained in the complete blood count (CBC). In fact, a CBC will be done obtaining the percentages and absolutes values of neutrophils, lymphocytes, monocytes, eosinophils and basophils. Neutrophil-to-lymphocyte and lymphocyte-to-monocyte ratios will be estimated.

  3. Inflammatory interleukines IL-6, IL-10 and IFN-γ quantification:

    Time frame: Week 0, 6, 8 and 16

    Cytokines IL6 and IL10 levels

  4. Intratumoral T Cells Infiltration in biopsies and resected tumors.

    Time frame: week 0, week 18/20 and week 26/28

    The density of each tumor-infiltrating immune cell (CD3 and CD8) will be assessed in biopsies and resected tumors.

  5. PERSONALIZED AI ASSISTED DOSIMETRY evaluation

    Time frame: week 0 to 26-28

    AI assisted dosimetry will be evaluated by the creation of a predictive model to assess treatment outcome based on planned and post-treatment high precision dose estimates. A prediction model based on corrected planning SPECT/CT and post-treatment PET/CT.

  6. ctDNA analysis: Identification of genetic alterations and circulating tumor DNA (ctDNA) monitoring through digital droplet PCR

    Time frame: week 6, 8, 12, 16, 22 and 30

    Sample collection and Nucleic acid isolation will be performed by means of Formalin-fixed paraffin embedded (FFPE) tumor biopsies (metastases). Two 10 mL Cell-Free DNA BCT ® CE (Streck) tubes of peripheral blood will be extracted for liquid biopsy studies. In FFPE tumour by NGS colorectal cancer cells are characterized by the acquisition of molecular alterations responsible for tumor development and progression. Digital droplet PCR (ddPCR) has emerged as an ultra-sensitive approach with various applications in the molecular diagnosis of tumors especially in liquid biopsy studies. KRAS, NRAS and BRAF mutation detection will be carried out.

  7. Macroscopic determination of the grade of necrosis

    Time frame: week 18/20 and week 26/28.

    the grade of necrosis will be analyzed through Histochemical staining of histological samples: standard hematoxylin-eosin staining. Staining of non-tumor liver with at least: Masson's trichrome and reticulin.

  8. Determination of the grade of necrosis: Microscopic study.

    Time frame: week 18/20 and week 26/28.

    The Microscopic report will include the number of nodules, size, distance to margin in mm, tumor regression grade and the lesions observed in the non-tumor liver parenchyma in resected tumors. With the presence or absence of viable tumor cells, it is advisable to report on the presence or absence of: Fibrosis, Necrosis, specifying whether it is of the normal or infarct-type and mucous extracellular.

  9. Evaluation of Post-treatment liver damage: Microscopic study

    Time frame: week 18/20 and week 26/28.

    Post-treatment liver damage: Presence and severity of steatosis, steatohepatitis and lesions related to the sinusoidal obstruction syndrome will be reported.

Study contacts

Contact information is provided by the study sponsor or research team.

Fernando Gómez, MD PhD

CONTACT

[email protected]

+34 628281300

Sponsors and collaborators

Lead sponsor

Fernando Gómez Muñoz

Other

Collaborators

  • Boston Scientific International S.A.
  • Instituto de Investigacion Sanitaria La Fe

Registry information

Official study title

Y90 Radioembolization as Neoadjuvant Therapy for Potentially Resectable Patients With Colorectal Liver Metastases: Immune Markers Evaluation, Impact on Circulating Tumor DNA and Personalized Dosimetry Approach

Acronym: YRENE

Important dates

Study start
2026
Primary completion
2028
Study completion
2028
First posted
Feb 12, 2026
Registry last updated
Feb 12, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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