HAI-Floxuridine, or Liver-Tx, Combined With 2nd Line Chemotherapy Versus 2nd Line Chemotherapy Alone for Patients With Colorectal Liver Metastases and Heavy Tumour Burden.

NCT04898504 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 33572
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with colorectal livermetasteses and heavy tumour burden and progression on 1st line chemotherapy have no other available treatment in Norway today other than 2nd line chemotherapy. The Investigators will randomize patients to HAI-floxuridine (FUDR), or liver-Tx, in addition to 2nd line chemotherapy versus 2nd line chemotherapy alone (Excalibur 1) or systemic chemotherapy with HAI/FUDR versus systemic chemotherapy alone (Excalibur 2). Primary endpoint is overall survival at 2yrs.

Conditions

Colorectal Cancer; Liver Metastases; Chemotherapy Effect

Keywords

HAI-floxuridine; 2nd line chemotherapy; Liver-Tx

Outcome Measures

Primary Outcomes (1)

• Overall survival at 2 years

  Patients with colorectal livermetasteses and insufficient respons on 1st line chemotherapy have a current OS of 14months from starting 2nd line chemotherapy. We want to see if any of or other treatment-arms will provide for a longer OS for these patients

  2 years

Secondary Outcomes (4)

• Quality of Life by using QLQ-C30

  At inclusion, and weeks, 6,12,24,36 and every 12 weeks until death or other illness-related incident.

• Operative complications

  Withion 30 days after surgery

• Postoperative morbidity and mortality

  30 and 90 days after surgery

• Quality of life using EQ-5D-5L

  At inclusion, and weeks, 6,12,24,36 and every 12 weeks until death or other illness-related incident.

Study Arms (3)

Next line chemotherapy only

NO INTERVENTION

Next line chemotherapy is the current standard treatment for patients with CRLM and progression on chemotherapy. We will include 18 patients in this treatment arm.

Liver transplant

ACTIVE COMPARATOR

Liver transplant (LTX) has emerged as a possible solution for some patients with unresectable CRLM who otherwise have good prognosis based on available scorings systems. We will include 9 patients in this treatment arm. They will be given next line chemotherapy followed by Liver-Tx.

Procedure: Liver Transplantation

Hepatic artery infusion (HAI) chemotherapy

ACTIVE COMPARATOR

The biological rationale for intra-arterial chemotherapy is that the hepatic artery rather than the portal vein is responsible for most of the blood supply to liver tumors. We will include 18 patients in this arm

Drug: Floxuridine

Interventions

Floxuridine DRUG

A laparotomy will be performed and a catheter placed in the hepatic artery Connected to a subcutaneous pump. This pump will be percutaneously filled with Floxuridine 6 times in 2 weeks cycles, alternating with heparin-solution.

Also known as: Hepatic artery Infusion Chemotherapy

Hepatic artery infusion (HAI) chemotherapy

Liver Transplantation PROCEDURE

Patients randomized to this arm will be given 2nd line chemotherapy (regimen given at the discression of the treating oncologist) followed by liver-Tx

Liver transplant

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The difference between 1 and 2 is the presence of a transplant alternative in Excalibur 1. For the purpose of prognosis stratification, patients in Excalibur 2 will be randomized in three strata (a, b and c). The intervention is identical, and they will be analysed as a merged group together with the corresponding groups of Excalibur 1.
• Included patients must fulfil the following criteria
• Primary histology: verified adenocarcinoma in colon or rectum
• Liver metastases
• Resection will require 10 % or more response in index lesions.
• And one of the following:
• Insufficient response on current line chemotherapy and in need of next line systemic chemotherapy or major change of active agents as judged by treating oncologist (I, IIa, IIb).
• Treatment stopped due to toxicity, and hence in need of next line systemic chemotherapy (I, IIa, IIb).
• Stable disease or partial response (RECIST) is achieved following first cycle of 1st. line conventional chemotherapy (4 doses), but minimal probability of reaching liver surgery (IIc) due to any of the following:
• i. \> 6 lesions with bi-lobar distribution and CEA \> 1.000, or ii. \> 10 lesions with bi-lobar distribution and at least one lesion with a diameter \> 5 cm, or iii. \> 15 lesions with bi-lobar distribution
• Chemotherapy
• If patients have commenced next line chemotherapy, randomization can only be allowed prior to first evaluation on next line chemotherapy regimen (I, IIa, IIb).
• For IIc, patients must have undergone one cycle of systemic conventional chemotherapy and only have stable disease or partial response at first evaluation, but with a response insufficient for resection.
• The patient
• Good performance status, ECOG 0 or 1.

You may not qualify if:

• Any of the following criteria will exclude participation in the trial:
• Arterial anatomy not suited for HAI pump-line insertion.
• A primary tumour in situ that is either a
• Rectal tumour scheduled for radiation therapy with fractionation 2 Gy x 25, or
• A right-sided or transverse colonic tumour
• Previous or current bone or CNS metastatic disease.
• Patients with known intolerance or allergy to any ingredient of the IMP to be used as standard therapy for that patient
• Breastfeeding women
• Patients with a psychiatric condition that makes participation in the trial impossible or unethical
• Patients in a poor nutritional state, those with depressed bone marrow function or those with potentially serious infections must be excluded.
• Any other reason why, in the opinion of the investigators, the patient should not participate.
• BRAF positivity
• Any sign of extra-hepatic metastatic disease or local recurrence on PET/CT scan, and on CT or MRI thorax/abdomen/pelvis dated within 6 weeks prior to the trial hospital MDT meeting (exception allowed for \<3 resectable lung lesions all \< 15mm).
• Liver lesion \>10cm
• Patient BMI \> 30

Sponsors & Collaborators

• Oslo University Hospital: lead

Study Sites (1)

Oslo University Hospital

Oslo, 0424, Norway

Location

Related Publications (13)

• Pak LM, Kemeny NE, Capanu M, Chou JF, Boucher T, Cercek A, Balachandran VP, Kingham TP, Allen PJ, DeMatteo RP, Jarnagin WR, D'Angelica MI. Prospective phase II trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. J Surg Oncol. 2018 Mar;117(4):634-643. doi: 10.1002/jso.24898. Epub 2017 Nov 22.

  PMID: 29165816 BACKGROUND

• Groot Koerkamp B, Sadot E, Kemeny NE, Gonen M, Leal JN, Allen PJ, Cercek A, DeMatteo RP, Kingham TP, Jarnagin WR, D'Angelica MI. Perioperative Hepatic Arterial Infusion Pump Chemotherapy Is Associated With Longer Survival After Resection of Colorectal Liver Metastases: A Propensity Score Analysis. J Clin Oncol. 2017 Jun 10;35(17):1938-1944. doi: 10.1200/JCO.2016.71.8346. Epub 2017 Apr 20.

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• D'Angelica MI, Correa-Gallego C, Paty PB, Cercek A, Gewirtz AN, Chou JF, Capanu M, Kingham TP, Fong Y, DeMatteo RP, Allen PJ, Jarnagin WR, Kemeny N. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg. 2015 Feb;261(2):353-60. doi: 10.1097/SLA.0000000000000614.

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  PMID: 28449055 BACKGROUND

• Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. doi: 10.1200/JCO.2010.33.5091. Epub 2011 Apr 18.

  PMID: 21502544 BACKGROUND

• Dueland S, Guren TK, Hagness M, Glimelius B, Line PD, Pfeiffer P, Foss A, Tveit KM. Chemotherapy or liver transplantation for nonresectable liver metastases from colorectal cancer? Ann Surg. 2015 May;261(5):956-60. doi: 10.1097/SLA.0000000000000786.

  PMID: 24950280 BACKGROUND

• Giacchetti S, Itzhaki M, Gruia G, Adam R, Zidani R, Kunstlinger F, Brienza S, Alafaci E, Bertheault-Cvitkovic F, Jasmin C, Reynes M, Bismuth H, Misset JL, Levi F. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol. 1999 Jun;10(6):663-9. doi: 10.1023/a:1008347829017.

  PMID: 10442188 BACKGROUND

• Brudvik KW, Bains SJ, Seeberg LT, Labori KJ, Waage A, Tasken K, Aandahl EM, Bjornbeth BA. Aggressive treatment of patients with metastatic colorectal cancer increases survival: a scandinavian single-center experience. HPB Surg. 2013;2013:727095. doi: 10.1155/2013/727095. Epub 2013 Jun 6.

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• Brudvik KW, Jones RP, Giuliante F, Shindoh J, Passot G, Chung MH, Song J, Li L, Dagenborg VJ, Fretland AA, Rosok B, De Rose AM, Ardito F, Edwin B, Panettieri E, Larocca LM, Yamashita S, Conrad C, Aloia TA, Poston GJ, Bjornbeth BA, Vauthey JN. RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases. Ann Surg. 2019 Jan;269(1):120-126. doi: 10.1097/SLA.0000000000002319.

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• Day RW, Brudvik KW, Vauthey JN, Conrad C, Gottumukkala V, Chun YS, Katz MH, Fleming JB, Lee JE, Aloia TA. Advances in hepatectomy technique: Toward zero transfusions in the modern era of liver surgery. Surgery. 2016 Mar;159(3):793-801. doi: 10.1016/j.surg.2015.10.006. Epub 2015 Nov 14.

  PMID: 26584854 BACKGROUND

Related Links

• Information about the study

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Floxuridine; Liver Transplantation

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxyuridine; Uridine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Digestive System Surgical Procedures; Surgical Procedures, Operative; Organ Transplantation; Transplantation

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of department

Model Details: 3 armed parallel RCT randomizing between 2nd line chemotherapy + HAI-floxuridine or liver-Tx versus 2nd line chemotherapy alone (Excalibur 1). 2-armed parallell design RCT between HAI/FUDR and 2nd line chemotherpy versus next line chemotherapy alone (Excalibur 2)

Study Record Dates

• First Submitted: May 10, 2021
• First Posted: May 24, 2021
• Study Start: August 23, 2021
• Primary Completion: May 1, 2025
• Study Completion: May 1, 2026
• Last Updated: November 7, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)