EXCALIBUR-2 is a two-armed RCT randomizing between 1) systemic chemotherapy + HAI/FUDR and 3) Systemic chemotherapy alone, i.e. current standard treatment.

Including patients with inoperable colorectal liver metastases who have insufficient response on current line chemotherapy and are hence planned for next line treatment (see inclusion/exclusion-criteria).

Following MDT potentially eligible patients will be evaluated at Rikshospitalet, Oslo University Hospital. If found eligible for inclusion and consent for participation patients will be randomized

HAI/FUDR: If randomized to HAI-Floxuridine patients will shortly after inclusion be given a date for operation for implantation of the pump. (Tricumed 1200V). The catheter is placed in the gastroduodenal artery via a laparotomy and the pump is placed subcutaneously on the patients abdomen. The pump is filled with heparinized NaCl. Day 3-5 after operation an angiography and a scintigraphy is performed to verify liver-only distribution of pump-content. Postoperative care is as following any laparotomy and patients are discharged to home in 4-7 days postoperatively. Day 14 after pump-placement the patients are scheduled at the outpatient-clinic, OUH, for the first cycle of Floxuridine (FUDR). Day 28 after pump-placement the patients return to outpatient-clinic, OUH for emptying of the pump and installation of heparinized NaCl. At this time the patients will also start systemic chemotherapy at their local hospital. The pump-treatment is repeated every 28 days (14 days Floxuridine in pump and 14 days heparinized NaCl). Every 8 weeks the patients are followed with QoL and CT-chest and abdomen and evaluated at MDT,OUH.

Radiographic examinations will routinely be performed at local hospital.

Side-effects HAI-FUDR:  Floxuridine has a 100% first-pass metabolism in the liver and is generally well tolerated with little side-effects. Serious side-effects will first and foremost be due to extra-hepatic distribution of Floxuridine eg. gastritis, gastric/duodenal ulcers, and pancreatitis. Therefore all patients are prescribed PPI`s and should continue PPI`s throughout the course of the pump-treatment. Secondly side-effects may be due to the catheter causing hepatic artery thrombosis or aneurism.

If any of the above mentioned conditions are diagnosed the pump-treatment will be stopped immediately. Therefore included patients with abdominal pain should seek immediate medical assistance for further investigation and the study-group consulted without delay. Some patients may experience toxic cholangitis (an inflammation of the bile ducts in the liver) and the steroid dexamethasone is therefore routinely added to the infusion of Floxuridine.

Systemic chemotherapy: Patients randomized to systemic chemotherapy will start next line chemotherapy at their local hospital. Blood-tests and clinical work-up will be obtained at their local-hospital every 14 days and collected by the study-group. Every 8 weeks (4 cycles) a CT-chest + abdomen will be taken and evaluated by MDT, OUH. QoL will be taken every 8 weeks.

Inclusion and Exclusion criteria

Note: 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

6.      Primary histology: verified adenocarcinoma in colon or rectum

7.      Liver metastases

a.       Not possible or feasible to resect at time of inclusion.
b.      Resection will require 10 % or more response in index lesions.
c.       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 (IIa, IIb).
·         Treatment stopped due to toxicity, and hence in need of next line systemic chemotherapy (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

8.      Chemotherapy

a.       Patients must have received at least one line of systemic chemotherapy at time of inclusion in the study. Planned for next line chemotherapy (IIa, IIb).
b.      If patients have commenced next line chemotherapy, randomization can only be allowed prior to first evaluation on next line chemotherapy regimen (IIa, IIb).
c.       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.

9.      The patient

a.       Good performance status, ECOG 0 or 1.
b.      Satisfactory blood tests: Hb >9 g/dl, neutrophiles >1.0 (after any G-CSF), TRC >75, Bilirubin<1.5 x upper normal level, ASAT, ALAT<5 x upper normal level, Creatinine <1.25 x upper normal level. Albumin above lower normal level.
c.       Women of childbearing potential (WOCBP) must have a confirmed menstrual cycle and a negative highly sensitive pregnancy test prior to inclusion, or two negative pregnancy tests two weeks apart
d.      WOCBP must agree to use a highly effective method of contraception (see section 6.1.2) for the entire period of exposure to the IMP in the trial, plus for one menstrual cycle/30 days after the last exposure due to the genotoxic potential of the IMP
e.       Men that may have sexual relations with a WOCBP during the trial must agree to use a condom during intercourse for the entire period of exposure plus for one sperm cycle / 90 days after the last exposure due to the genotoxic potential of the IMP

10.  Signed informed consent and expected cooperation of the patients for treatment and follow up must be obtained and documented according to GCP, and national/local regulations.

Exclusion Criteria

Any of the following criteria will exclude participation in the trial:

16.  Arterial anatomy not suited for HAI pump-line insertion.

17.  A primary tumour in situ that is either a

a.       Rectal tumour scheduled for radiation therapy with fractionation 2 Gy x 25, or
b.      A right-sided or transverse colonic tumour

18.  Previous or current bone or CNS metastatic disease.
19.  Patients with known intolerance or allergy to any ingredient of the IMP to be used as standard therapy for that patient
20.  Breastfeeding women
21.  Patients with a psychiatric condition that makes participation in the trial impossible or unethical
22.  Patients in a poor nutritional state, those with depressed bone marrow function or those with potentially serious infections must be excluded.

23.  Any other reason why, in the opinion of the investigators, the patient should not participate.

Stratification of Excalibur II:

For patients eligible for Excalibur II, randomization will be in stratum:
IIa for patients following a switch to next-line chemotherapy with none of the following features, and
IIb for patients following a switch to next-line chemotherapy with any of the following features
IIc for patients still on 1st line chemotherapy with none or any of the following features

·         Non-curable pulmonary disease
·         Non-hilar, non-regional lymph node metastases
·         Limited and resectable peritoneal disease