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

Sponsor

Hospital Vall d'Hebron (Other)

Overall Status

Recruiting

CT.gov ID

NCT05398380

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Liver Metastases Genetic Change	Other: Liver transplantation	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

35 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2022

Anticipated Primary Completion Date :

Dec 31, 2026

Anticipated Study Completion Date :

Dec 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transplantation Liver transplantation for the treatment of unresectable colorectal cancer liver metastases	Other: Liver transplantation Liver transplantation

Arm

Intervention/Treatment

Experimental: Transplantation

Liver transplantation for the treatment of unresectable colorectal cancer liver metastases

Other: Liver transplantation

Liver transplantation

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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.

Other Outcome Measures

Percentage of the intratumoral genetic heterogeneity of the metastatic liver through an in-depth lineage study [On day of transplantation]
High-throughput single-cell RNA sequencing (scRNA-seq) will allow deep phenotyping of cells, allowing detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages from the metastatic liver removed to the recurrence (hepatic or extrahepatic).
Percentage of patients with circulating tumor DNA (ctDNA) [5 years]
ctDNA monitorization will be performed pre-chemotherapy, pre-transplantation and every three months after transplantation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Willing and able to provide written informed consent.
Male or female, aged 18-70 years old inclusive at study entry.
ECOG (Eastern Cooperative Oncology Group) 0 or 1.
Histologically-proven primary colorectal tumor.
Bilateral, limited at liver and non-resectable CRLM by consensus in Multidisciplinary Committee.
Resection of primary colorectal tumor according oncological principles and adequate TNM stage.
Time from primary colorectal tumor resection to transplant ≥ 12 months.
Primary colorectal tumor stage ≤ T3N1. If time between primary tumor resection is ≥ 2 years, stage T4N0 or T4N2 is accepted.
No signs of extrahepatic metastatic disease according to PET/CT scan, CT and pelvic MRI.
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.
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.
CEA (Carcinoembryonic antigen) values ≤ 80 µg/L immediately prior to screening.
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

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.

Exclusion Criteria:

Largest Lesion >5.5cm immediately prior to screening
Patients with Lynch Syndrome
BRAF mutation and/or primary tumor of microsatellite instability (MSI)
Recurrence of primary tumor confirmed by colonoscopy or pelvic MRI within the last 12 months prior to screening.
Previous or concurrent cancer in the last 5 years. Any cancer curatively treated 5 years prior to entry or treated basal cell carcinoma is permitted.
Substance abuse, medical, psychological or social conditions that may interfere with the patient´s participation in the study or evaluation of the study results.
Cardiac or pulmonary disease uncontrolled as contraindication for any surgical procedure.
Active infection.
Pregnant or breast-feeding patients
Any reason why in the opinion of the investigator, the patient should not participate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of HPB Surgery and Transplants, Hospital Vall d´Hebron	Barcelona		Spain	08035

Sponsors and Collaborators

Hospital Vall d'Hebron

Investigators

Principal Investigator: Ramón Charco, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Principal Investigator: Elena Elez, Department of Oncology, Hospital Universitario Vall d´Hebron
Principal Investigator: Cristina Dopazo, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Study Chair: Ernest Hidalgo, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Study Chair: Itxarone Bilbao, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Study Chair: Concepción Gómez-Gavara, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Study Chair: Mireia Caralt, Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron
Study Chair: Javier Ros, Department of Oncology, Hospital Universitario Vall d´Hebron
Study Chair: Francesc Salva, Department of Oncology, Hospital Universitario Vall d´Hebron
Study Chair: Isabel Campos-Varela, Liver Unit, Department of Internal Medicine, Hospital Universitario Vall d´Hebron
Study Chair: Lluis Castells, Liver Unit, Department of Internal Medicine, Hospital Universitario Vall d´Hebron