Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04898504 |
| Other study ID # |
33572 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
August 23, 2021 |
| Est. completion date |
May 2026 |
Study information
| Verified date |
August 2023 |
| Source |
Oslo University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
1.1 Background - Disease Colorectal cancer (CRC) is the second most frequent malignant
disease in Norway (Cancer in Norway 2017). About 50% of the patients will have metastatic
disease at time of diagnosis or develop metastatic disease later on. Liver metastases are the
most frequent site of metastatic disease. Liver resection is considered the only curative
treatment option in CRC patients with liver metastases, however only about 20% of the
patients are candidates for liver resection. The treatment option for the majority of the
patients is palliative chemotherapy with median overall survival from start of chemotherapy
of about 2 years and 10-12 months from starting second line chemotherapy.
1.2 Liver resections for Colorectal Liver metastases (CRLM) While high-quality data
(randomized trials) are lacking, it is generally accepted that the only curative treatment
for colorectal liver metastases (CRLM) is surgery. Liver resections are generally well
tolerated and safe 1, but some patients recur early and probably have limited or no benefit
from surgery. These are hard to identify upfront. Even following three decades of systematic
liver surgery for CRLM, there is a lack of robust prognostic scoring systems that have
sufficient discriminatory power to serve as selectors for surgery or non-operative treatment
2, 3. Even among patients with very poor prognostic scores, there are some who will survive
five years following surgery 4, and even without surgery 5. Over the decades, the definition
of resectability/un-resectability has been steadily modified. Today, any configuration of
metastases can be deemed resectable as long as a resection will leave behind a working liver
volume of at least 20-30 % of the estimated total liver volume with a functioning arterial
inflow, portal venous inflow, draining bile duct and draining hepatic vein.
1.3 The grey zone As resections are generally well tolerated and adequate prognostication is
wanting, there is a tendency to offer resections to patients who have borderline resectable
CRLM or who exhibit other non-favourable traits like large or multiple metastases. For
patients who have early recurrence of disease, such resections represent a net loss of
quality-of-life and an unwanted expenditure for society. Exploring the optimal treatment
modality for patients in this grey zone, i.e. with uncertain benefit from surgery, is
important to avoid unnecessary resections and providing the optimal treatment for patients in
a critical situation.
1.4 Systemic chemotherapy for CRLM Palliative chemotherapy is in general the only treatment
option for the vast majority of non-resectable patients. The expected median overall survival
(OS) from start of first line chemotherapy is about 2 years and the 5 years OS is about 10%,
although, longer median OS has been obtained in selected patients with good performance
status (ECOG 0-1), no (K)RAS or BRAF mutations and left-sided tumors 6-10. OS from start of
second line chemotherapy is 10-12 months 11.
1.5 Liver transplant for CRLM 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 12, 13. In patients with non-resectable liver only metastases the
investigators have previously shown 5 year OS of 56% compared to 9% in a similar cohort of
patients starting first line chemotherapy 6, but due to lack of donor organs this will never
become the backbone of any treatment modality for a disease as prevalent as CRLM. However,
LTX is probably the best treatment option in highly selected patients with non-resectable
CRLM liver only disease.
1.6 Hepatic artery infusion (HAI) chemotherapy for CRLM 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. Hepatic Artery Infusion (HAI) of a
cytotoxic drug floxuridine (FUDR) that has a very high first-pass extraction (ca 95 %) in the
liver has shown promising results in selected series for several decades 14-16. It was
developed at Memorial Sloan Kettering Cancer Center (MSKCC, New York, USA) but is currently
unavailable in the European Union, because floxuridine is not registered. HAI has however not
gained foothold as a standard treatment option for CRLM, and most publications stem from a
very few centres. The reasons for this lack of dissemination are unknown but could well be
related to the complexity of the treatment algorithm and the lack of modern randomized
trials. In Europe several centers in The Nederlands have recently started the HAI treatment
procedure as adjuvant treatment in CRC patients who have received liver resection. (Buisman
FE et al. Ann. Surg. Oncol. 2019 26: 4599-4607. Of the 20 patients included in the study in
The Nederlands two patients had Clavien-Dindo complication grade III with reoperation due to
replacement of a pump with slow flow-rate and a flipped pump. The treatment administered both
at MSKCC and the two centers in The Nederlands consist of 0.12 mg FUDR/kg/day + 35.000 IE
heparin + 25 mg dexamethasnone in a total volume of 35ml NaCL administered as a continue
infusion for 14 days with dose reduction if liver function is affected (Table 2). At day 15
the pump is emtied and refiled with a low dose heparin solution for continuous infusion to
avoid coagulation of the catheter. A new cycle is started at day 29. The HAI treatment has
been combined with both oxaliplatin and irinotecan regimens combined with 5-FU as systemic
chemotherapy 14,16,17 .HAI has also been combined with systemic gemcitabine-oxaliplatin
regimen in patients with non-resectable intrahepatic cholangiocarcinoma18 In the study by
D'Angelica in non-resectable CRC patients the response rate was 76%, median overall survival
was 38 months and 23 of 49 patients became resectable and received a liver resection.
Patients having a liver resection had a 3 year overall survival of 80%. In the study by Pak
33 of 64 non-resectable CRC patients received a liver resection with 5 year overall survival
of 36%. These results are better compared to what has been reported by systemic chemotherapy
only with median overall survival of about 24 months in most studies. Optimal treatment for
patients with CRLM in the grey zone is therefore not yet defined and there is a definte need
for further studies.
To optimize treatment for patients with a large tumour burden and borderline resectability,
the investigators will compare three treatment modalities in a randomized controlled trial in
patients that have progressive disease on 1st line of chemotherapy treatment.
1.7 Rationale for the Study and Purpose The target population for this study will be patients
who based on traditional preoperative criteria have a very dismal prognosis. They will -
according to the inclusion criteria - have a large tumour burden and have shown progression
on 1st line systemic chemotherapy treatment. Based on previous trials, only 30 % of this
patient group will be alive after two years. These patients have today only one treatment
modality available: 2nd line systemic chemotherapy. Response can, however, only be expected
in a small minority of these patients. As of today, they are not acceptable for inclusion
into any of the liver transplant protocols, and hepatic aretery infusion (HAI) chemotherapy
treatment is not offered in Norway (or any other European country, save the Netherlands, as
far as the investigators know).
With such a dismal outcome for these patients, an alternative modality that has the potential
to improve survival is highly warranted. While transplantation has such a potential, the
access to donor organs will allways limit the real-life use of such a treatment and the
inclusion of a transplant group in this trial is primarily for proof-of-principle reasons: to
benchmark what the investigators have reason to believe is the optimal treatment.
The use of HAI chemotherapy with FUDR has some inherent risks. A laparotomy is necessary to
apply the catheter and intra hepatic infusion of FUDR has been reported to cause biliary
inflammation and necrosis in a small fraction of the patients. The risk for the latter is
however significantly reduced by concommittant steroid infusion. The experiences published
from the MSKCC (se further) does however suggest that the drug has few systemic side effects
as the first-pass effect in the liver is close to complete, i.e. there is minimal release of
active drug into the systemic circulation.
The IMP for use in this protocol does not have a marketing authorization in Europa. The
institution that has pioneered the HAI treatment in CRC is Memorial Sloan Kettering Hospital
(MSKCC) in New York and the dose is identical to the dose that used in several studies from
MSKCC 14,16 and The Nederlands17.
1.8 Research hypothesis In patients with large tumour burden and/or borderline resectability
of colorectal liver metastases and progression on 1st line systemic chemotherapy, overall
survival following systemic therapy combined with hepatic artery infusion chemotherapy (HAI),
or liver transplantation, is better than following conventional systemic chemotherapy alone.
