Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

Clinical Impact of Molecular Biomarkers in Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

Status

Recruiting

Phases

Unknown

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05398380

Enrollment

Registered

2022-06-01

Start date

2022-01-01

Completion date

2026-12-31

Last updated

2026-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Colorectal Cancer, Genetic Change, Liver Metastases

Keywords

Liver Transplantation, Non-resectable colorectal liver metastases, Tumoral biomarkers, Translational research

Brief summary

The patients with non-resectable colorectal liver metastases (CRLM) have always being considered a particular subgroup of CRLM in which the therapeutic approach, is focused on strategies that allow a potential surgery like neoadjuvant systemic treatments. But, the underlying biology that causes this particular profile of spread in a proportion of patients that always recur and progress in the liver has not been properly characterized from a biological point of view. Unfortunately, these patients finally develop liver metastasis not amenable for local treatments and become refractory to systemic treatments even without developing extrahepatic liver metastases. As a result, liver transplantation (LT) is a potential for patients without extrahepatic involvement and nonresectable CRLM. There are several studies that aims to evaluate if LT increases overall survival compared to best alternative care. To our knowledge, none of these studies incorporate objectives focused on the underlying tumor biology of this particular population and the development of focused strategies including a dynamic disease monitoring and targeted treatments for this particular population.The METLIVER trial will permit to expand the genetic studies to the whole complexity of metastatic lesions and a more precise evaluation of their genetic heterogeneity. Moreover, it will help to precise the type of genetic analyses on liquid biopsies that can be designed for patients that will unfortunately relapse mostly with lung metastases after LT. Our proposal will maximize the opportunity to produce an unprecedented knowledge on CRLM evolution and will provide new opportunities for relapsed patients.

Detailed description

A prospective multicenter Spanish clinical phase II trial is proposed. The study population will consist of male and female with non-resectable CRLM, who are 18 to 70 years old, inclusive, at the time of providing informed consent. Patients will be identified, treated and followed by the clinical investigators within the different centers included in the present study. Those patients deemed unresectable CRLM by consensus in multidisciplinary meeting will be pre-screened for eligibility to be included in the study. After receiving the corresponding chemotherapy and if the patient meets the inclusion criteria and none of the exclusion criteria will sign the informed consent and will be evaluated for liver transplantation according to institutional protocols at the transplant unit. Patients eligible for liver transplantation will continue chemotherapy until the time of an organ is available. However, patients receiving treatment with bevacizumab or aflibercept will discontinue this treatment at time of inclusion in waiting list. If there are no further contraindications at the time of transplantation, laparotomy including tumor staging will be performed and if there is no sign of extrahepatic disease, liver transplantation will continue according to institutional protocols. Participants will be followed for 5 years and monitored for safety, survival and disease recurrence. Regarding the translational research: * The metastatic liver removed on day of transplant will be analysed using high-throughput single-cell RNA sequencing (scRNA-seq) which will allow deep phenotyping of cells for detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages. * RAS allele fraction will be monitored by BEAMing and it will be performed before chemotherapy treatment, before LT, post-transplantation, and every 3 months until the patient relapses if relapses.

Interventions

OTHERLiver transplantation

Liver transplantation

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

1. Willing and able to provide written informed consent. 2. Male or female, aged 18-70 years old inclusive at study entry. 3. ECOG (Eastern Cooperative Oncology Group) 0 or 1. 4. Histologically-proven primary colorectal tumor. 5. Bilateral, limited at liver and non-resectable CRLM by consensus in Multidisciplinary Committee. 6. Resection of primary colorectal tumor according oncological principles and adequate TNM stage. 7. Time from primary colorectal tumor resection to transplant ≥ 12 months. 8. Primary colorectal tumor stage ≤ T3N1. If time between primary tumor resection is ≥ 2 years, stage T4N0 or T4N2 is accepted. 9. No signs of extrahepatic metastatic disease according to PET/CT scan, CT and pelvic MRI. 10. The patient has undergone systemic chemotherapy for a minimum of 3 months at the time of screening and maximum of 2 lines of fluoropyrimidine based chemotherapy combined or not with irinotecan or oxaliplatin associated or no not with targeted therapy based in molecular biomarkers. 11. Demonstrated stability or partial regression of CRLM following RECIST criteria v 1.1., at minimum 3 months since the last treatment received and immediately prior to screening. 12. CEA (Carcinoembryonic antigen) values ≤ 80 µg/L immediately prior to screening. 13. Adequate blood test regarding: * Creatinine ≤1.25 x upper normal level or estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73m2 using following the Chronic Kidney disease epidemiology collaboration (CKD-EPI) formula. * Platelets ≥80 × 109/L * Neutrophiles ≥ 2.5 × 109/L 14. Patients with hepatic failure after resection will be considered if it occurs as a consequence of an inadequate preoperative estimation of the functional volume that would have contraindicated the surgery. They should meet the inclusion criteria and none of the

Exclusion criteria

Design outcomes

Primary

Measure	Time frame	Description
Five years overall survival	5 years	Percentage of subject who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up

Secondary

Measure	Time frame	Description
One and three years overall survival	1 and 3 years	Percentage of subjects who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up
One, three and five years recurrence free survival	1, 3 and 5 years	Percentage or patients who did not progress from transplantation until death or last follow-up analysed using Kaplan-Meier and the log-rank test.
Number of patients that drop-out of the study prior to receive intervention	Prior to liver transplantation	Percentage of patients that drop-out of the study prior to liver transplantation
Patterns of cancer recurrence after liver transplantation	5 years	Defined as porcentage of patients with hepatic recurrence, extrahepatic recurrence or both
Changes in quality of life assessed by EORTC QLQ-C30 questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30)	5 years	These questions allowed categorizing patients into whether they exhibited a clinically important symptom/functional impairment for each scale from 1 (not at all) to 4 (very much). It would be assessed pretransplantation and every 6 months after transplantation.

Countries

Spain

Contacts

CONTACTCRISTINA DOPAZO, MD/PhD

cristina.dopazo@vallhebron.cat+34932746113

CONTACTCRISTINA DOPAZO

cristina.dopazo@vallhebron.cat+34932746113

PRINCIPAL_INVESTIGATORRamón Charco