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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Liver Metastases; Genetic Change
• Intervention / Treatment: Other: Liver transplantation

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 Type: Interventional
• Enrollment (Estimated): 35
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: CRISTINA DOPAZO, MD/PhD; Phone Number: +34932746113; Email: cristina.dopazo@vallhebron.cat
• Study Contact Backup: Name: CRISTINA DOPAZO; Phone Number: +34932746113; Email: cristina.dopazo@vallhebron.cat

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Department of HPB Surgery and Transplants, Hospital Vall d´Hebron
    • Contact: Cristina Dopazo, PhD/MD; Phone Number: 6113 +34932746000; Email: cristina.dopazo@vallhebron.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Exclusion Criteria:

1. Largest Lesion >5.5cm immediately prior to screening
2. Patients with Lynch Syndrome
3. BRAF mutation and/or primary tumor of microsatellite instability (MSI)
4. Recurrence of primary tumor confirmed by colonoscopy or pelvic MRI within the last 12 months prior to screening.
5. 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.
6. Substance abuse, medical, psychological or social conditions that may interfere with the patient´s participation in the study or evaluation of the study results.
7. Cardiac or pulmonary disease uncontrolled as contraindication for any surgical procedure.
8. Active infection.
9. Pregnant or breast-feeding patients
10. Any reason why in the opinion of the investigator, the patient should not participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One and three years overall survival	Percentage of subjects who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up	1 and 3 years
One, three and five years recurrence free survival	Percentage or patients who did not progress from transplantation until death or last follow-up analysed using Kaplan-Meier and the log-rank test.	1, 3 and 5 years
Number of patients that drop-out of the study prior to receive intervention	Percentage of patients that drop-out of the study prior to liver transplantation	Prior to liver transplantation
Patterns of cancer recurrence after liver transplantation	Defined as porcentage of patients with hepatic recurrence, extrahepatic recurrence or both	5 years
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)	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.	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of the intratumoral genetic heterogeneity of the metastatic liver through an in-depth lineage study	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).	On day of transplantation
Percentage of patients with circulating tumor DNA (ctDNA)	ctDNA monitorization will be performed pre-chemotherapy, pre-transplantation and every three months after transplantation	5 years

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, Knudsen M, Nordentoft I, Wu HT, Tin AS, Heilskov Rasmussen M, Vang S, Shchegrova S, Frydendahl Boll Johansen A, Srinivasan R, Assaf Z, Balcioglu M, Olson A, Dashner S, Hafez D, Navarro S, Goel S, Rabinowitz M, Billings P, Sigurjonsson S, Dyrskjot L, Swenerton R, Aleshin A, Laurberg S, Husted Madsen A, Kannerup AS, Stribolt K, Palmelund Krag S, Iversen LH, Gotschalck Sunesen K, Lin CJ, Zimmermann BG, Lindbjerg Andersen C. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. 2019 Aug 1;5(8):1124-1131. doi: 10.1001/jamaoncol.2019.0528. Erratum In: JAMA Oncol. 2019 Jun 13;:
• Dueland S, Grut H, Syversveen T, Hagness M, Line PD. Selection criteria related to long-term survival following liver transplantation for colorectal liver metastasis. Am J Transplant. 2020 Feb;20(2):530-537. doi: 10.1111/ajt.15682. Epub 2019 Nov 28.
• Elez E, Chianese C, Sanz-Garcia E, Martinelli E, Noguerido A, Mancuso FM, Caratu G, Matito J, Grasselli J, Cardone C, Esposito Abate R, Martini G, Santos C, Macarulla T, Argiles G, Capdevila J, Garcia A, Mulet N, Maiello E, Normanno N, Jones F, Tabernero J, Ciardello F, Salazar R, Vivancos A. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. Mol Oncol. 2019 Sep;13(9):1827-1835. doi: 10.1002/1878-0261.12547. Epub 2019 Jul 31.
• Bonney GK, Chew CA, Lodge P, Hubbard J, Halazun KJ, Trunecka P, Muiesan P, Mirza DF, Isaac J, Laing RW, Iyer SG, Chee CE, Yong WP, Muthiah MD, Panaro F, Sanabria J, Grothey A, Moodley K, Chau I, Chan ACY, Wang CC, Menon K, Sapisochin G, Hagness M, Dueland S, Line PD, Adam R. Liver transplantation for non-resectable colorectal liver metastases: the International Hepato-Pancreato-Biliary Association consensus guidelines. Lancet Gastroenterol Hepatol. 2021 Nov;6(11):933-946. doi: 10.1016/S2468-1253(21)00219-3. Epub 2021 Sep 8. Erratum In: Lancet Gastroenterol Hepatol. 2021 Nov;6(11):e7.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 20, 2022
• First Submitted That Met QC Criteria: May 25, 2022
• First Posted (Actual): June 1, 2022

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 28, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Liver Transplantation; Translational research; Non-resectable colorectal liver metastases; Tumoral biomarkers
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Neoplastic Processes; Neoplasm Metastasis; Liver Neoplasms
• Other Study ID Numbers: METLIVER Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No