Overview
Sponsor-declared trial summary
Phase
Therapeutic exploratory (Phase II)
Status
Temporarily halted
Participants planned
97
Countries
1
Sites
1
Colorectal Liver Metastases
Overall survival 2 years
Key facts
- Sponsor
- Oslo University Hospital HF
- Participant type
- Patients
- Age range
- 18-64 years, 65+ years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Digestive System Diseases [C06], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Phenomena and Processes [G] - Digestive System and Oral Physiological Phenomena [G10]
- Trial duration
- 21 May 2026 → ongoing
- Decision date (initial)
- 2024-07-15
- Transition trial
- Yes
- Low-intervention
- No
- Rare-disease indication
- No
- Vulnerable population
- No
External identifiers
- EU CT number
- 2024-512397-95-00
- EudraCT number
- 2019-002388-87
- ClinicalTrials.gov
- NCT04898504
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy, Safety, Dose response
Overall survival 2 years
Conditions and MedDRA coding
Colorectal Liver Metastases
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 5
- Primary histology: verified adenocarcinoma in colon or rectum
- 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: I 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). II Treatment stopped due to toxicity, and hence in need of next line systemic chemotherapy (I, IIa, IIb). III 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: a. Patients must have received at least one line of systemic chemotherapy at time of inclusion in the study. Planned for next line chemotherapy (I, IIa, IIb). b. If patients have commenced next line chemotherapy, randomization can only be allowed prior to first evaluation on next line chemotherapy regimen (I, 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.
- 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
- 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 9
- Arterial anatomy not suited for HAI pump-line insertion.
- 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
- 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.
- Exclusion Excalibur I: Any of the following will preclude inclusion into Excalibur I (but not into Excalibur IIa/b/c): 1. BRAF positivity 2. 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). 3. Liver lesion >10cm 4. Patient BMI > 30 5. Any previous non-colorectal malignancy within latest five years with the exception of basal cell carcinoma of the skin. 6. Age > 70 years 7. Liver metastatic ingrowth to the diaphragm determined by CT-scan and/or MRI/or ultrasound 8. Any primary tumour in situ
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- Overall Survival at two years
Secondary endpoints 4
- Progression-free survival
- Overall survival at 5 years
- Resection/transplantation rate
- Quality of life
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 5
PRD10652670 · Product
- Active substance
- Floxuridine
- Substance synonyms
- 2'-DEOXY-5-FLUOROURIDINE, 5-FLUORO-2'-DEOXYURIDINE
- Pharmaceutical form
- POWDER FOR SOLUTION FOR INJECTION
- Route of administration
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Max daily dose
- 0.12 mg/kg milligram(s)/kilogram
- Max total dose
- 1.68 mg/kg milligram(s)/kilogram
- Max treatment duration
- 2 Week(s)
- Authorisation status
- Not Authorised
- MA holder
- OSLO UNIVERSITY HOSPITAL
- Paediatric formulation
- No
- Orphan designation
- No
SUB02475MIG · Substance
- Active substance
- Heparin
- Pharmaceutical form
- INTRAVENOUS INFUSION
- Route of administration
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Max daily dose
- 1500 IU international unit(s)
- Max total dose
- 21000
- Max treatment duration
- 2 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP100373670 · ATC
- Active substance
- Heparin
- Substance synonyms
- HEPARIINI, HEPARINUM
- Route of administration
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Max daily dose
- 1500 U unit(s)
- Max total dose
- 21000
- Max treatment duration
- 14 Day(s)
- Authorisation status
- Authorised
- ATC code
- B01AB01 — HEPARIN
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
SCP10332310 · ATC
- Active substance
- Dexamethasone Acetate
- Route of administration
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Max daily dose
- 1.1 mg milligram(s)
- Max total dose
- 15 mg milligram(s)
- Max treatment duration
- 14 Day(s)
- Authorisation status
- Authorised
- ATC code
- H02AB02 — DEXAMETHASONE
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Dexamethasone Sodium Phosphate
SUB01615MIG · Substance
- Active substance
- Dexamethasone Sodium Phosphate
- Pharmaceutical form
- SOLUTION FOR INJECTION
- Route of administration
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Max daily dose
- 1 mg milligram(s)
- Max total dose
- 15 mg milligram(s)
- Max treatment duration
- 2 Week(s)
- Authorisation status
- Authorised
- ATC code
- - — -
- Marketing authorisation
- -
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Oslo University Hospital HF
- Sponsor organisation
- Oslo University Hospital HF
- Address
- Taarnbygget, Kirkeveien 166 Kirkeveien 166
- City
- Oslo
- Postcode
- 0450
- Country
- Norway
Scientific contact point
- Organisation
- Oslo University Hospital HF
- Contact name
- Kristoffer Lassen
Public contact point
- Organisation
- Oslo University Hospital HF
- Contact name
- Kristoffer Lassen
Locations
1 EU/EEA country · 1 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Norway | Temporarily halted | 97 | 1 |
| Rest of world | — | 0 | — |
Investigational sites
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Norway | 2021-05-20 | 2024-07-15 | 2024-09-17 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Temporary halts 2 · Art. 38 CTR
Temporary halt TH-135090
- Halt date
- 2024-09-17
- Member states concerned
- Norway
- Publication date
- 2026-05-21
- Reason
- Safety related (clinical or pre-clinical results)
- Explanation
- See documents submitted in September 2024 for more information.
As of April 2025 there are no longer any patients in the Excalibur trial receiving Floxuridine by the pump. - Follow-up measures
- See documents submitted in September 2024. All systemic doses of 5-FU and most other systemic chemotherapy was reduced. As of September 2024 there where still three patients receving Floxuridine by the pump. By April 2025 this number was zero.
- Benefit-risk balance changed
- Yes
- Treatment stopped
- Yes
Temporary halt TH-46746
- Halt date
- 2024-09-17
- Planned restart
- 2024-10-08
- Member states concerned
- Norway
- Publication date
- 2024-09-17
- Reason
- Safety related (clinical or pre-clinical results)
- Explanation
- Patients included in the Excalibur randomised trial who are in the intervention group receive Floxuridine intra-arterially via pump and catheter (see protocol). Floxuridine has a near complete first-pass metabolism in the liver and systemic effects are reported to be absolutely minimal. As a result, high doses can be used directly into the liver. As these patients have extensive cancers, they are also treated concomitantly with systemic 5FU-based chemotherapy regimens.
Enterocolitis is a well described adverse effect of several systemic chemotherapy regimens. Over the years we have seen some cases of moderate and even very serious enterocolitis in patients in the intervention groups. Two patients have been treated in the ICU. As we had no reason at the time to suspect any interaction with Floxuridine provided by pump, we viewed these complications as a consequence of the systemic (standard) treatment, but Floxuridine was always removed from the pump in these instances.
Two weeks ago, we concluded that the incidence and severity of enterocolitis in the intervention group was worryingly high. We consulted pharmacologists dedicated to such situations and asked for expedite review. On 12 September they returned with a hypothesis for a possible cause-effect relationship between un-reduced doses of systemic fluouracil (5FU) and pump administered floxuridine. At that date we concluded that previous cases of enterocolitis were not to be regarded as caused by the standard treatment alone - Follow-up measures
- We decided on 5 September (based on suspicion) an immediate reduction in doses of systemic 5FU to 80% and that initial bolus should be omitted in all patients receiving floxuridine by pump. This was corroborated by the 12 September pharmacology report. This reduction is in line with the current US EA-2222/pump protocol (inclusion commenced March 20249 that we had mailed from their P.I. on 16 September.
All participating oncologists are being informed that systemic 5FU should be administered without bolus and in 80% doses in patients under active Floxuridine treatment – presently three patients in total. One patient is presently under treatment from enterocolitis and not receiving any further chemotherapy until this has resolved. As before, pumps are emptied of Floxuridine in any case of diarrhoea.
Trial inclusion is temporarily halted on 17 September as reports are submitted. The protocol will be updated and new approval solicited. - Benefit-risk balance changed
- Yes
- Treatment stopped
- No
Urgent safety measures 1 · Art. 54 CTR
Urgent safety measure US-46743
- Event date
- 2024-09-12
- Submission date
- 2024-09-17
- In response to
- SUSAR
- Member states affected
- Norway
- Event description
- Patients included in the Excalibur randomised trial who are in the intervention group receive Floxuridine intra-arterially via pump and catheter (see protocol). Floxuridine has a near complete first-pass metabolism in the liver and systemic effects are reported to be absolutely minimal. As a result, high doses can be used directly into the liver. As these patients have extensive cancers, they are also treated concomitantly with systemic 5FU-based chemotherapy regimens.
Enterocolitis is a well described adverse effect of several systemic chemotherapy regimens. Over the years we have seen some cases of moderate and even very serious enterocolitis in patients in the intervention groups. Two patients have been treated in the ICU. As we had no reason at the time to suspect any interaction with Floxuridine provided by pump, we viewed these complications as a consequence of the systemic (standard) treatment, but Floxuridine was always removed from the pump in these instances.
Two weeks ago, we concluded that the incidence and severity of enterocolitis in the intervention group was worryingly high. We consulted pharmacologists dedicated to such situations and asked for expedite review. On 12 September they returned with a hypothesis for a possible cause-effect relationship between un-reduced doses of systemic fluouracil (5FU) and pump administered floxuridine. At that date we concluded that previous cases of enterocolitis were not to be regarded as caused by the standard treatment alone. - Measures taken
- We decided on 5 September (based on suspicion) an immediate reduction in doses of systemic 5FU to 80% and that initial bolus should be omitted in all patients receiving floxuridine by pump. This was corroborated by the 12 September pharmacology report. This reduction is in line with the current US EA-2222/pump protocol (inclusion commenced March 20249 that we had mailed from their P.I. on 16 September.
All participating oncologists are being informed that systemic 5FU should be administered without bolus and in 80% doses in patients under active Floxuridine treatment – presently three patients in total. One patient is presently under treatment from enterocolitis and not receiving any further chemotherapy until this has resolved. As before, pumps are emptied of Floxuridine in any case of diarrhoea.
Trial inclusion is temporarily halted on 17 September as reports are submitted. The protocol will be updated and new approval solicited.
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 4 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol 2024-512397-95-00 | 7.0 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC Dexamethasone | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC FUDR | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E2_SmPC HEPARIN | 1 |
Application history
2 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2024-06-14 | Norway | Acceptable 2024-07-12
|
2024-07-15 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2026-05-18 | Norway | Acceptable 2026-05-20
|
2026-05-20 |