Clinical Trial Results:
5-Fluorouracil (5-FU), folinic acid and irinotecan (FOLFIRI) versus 5-FU and folinic acid as second-line chemotherapy in patients with biliary tract cancer (IRIBIL): a randomized open-label phase 2 study
|
Summary
|
|
EudraCT number |
2015-004028-69 |
Trial protocol |
DE |
Global end of trial date |
31 Oct 2024
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
07 Nov 2025
|
First version publication date |
07 Nov 2025
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
IRIBIL
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
DRKS: DRKS00012595 | ||
|
Sponsors
|
|||
Sponsor organisation name |
Goethe University Frankfurt
|
||
Sponsor organisation address |
Theodor-Stern-Kai 7, 60590 / Frankfurt, Germany,
|
||
Public contact |
Studienambulanz Medizinische Klinik 1, Universitätsklinikum der Goethe-Universität Frankfurt, +49 (0)696301-87769, Finkelmeier@med.uni-frankfurt.de
|
||
Scientific contact |
Studienambulanz Medizinische Klinik 1,, Universitätsklinikum der Goethe-Universität Frankfurt, +49 (0)696301-87769, Finkelmeier@med.uni-frankfurt.de
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
05 Sep 2025
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
31 Oct 2024
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
31 Oct 2024
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
• Determination of the progression free survival (PFS) in FOLFIRI arm > 2 months
|
||
Protection of trial subjects |
Second-line systemic chemotherapy is performed regularly in patients progressing under first-line therapy. After failure of Gemcitabin and Cisplatin antineoplastic therapies are commonly switched to 5-FU based second-line therapies. 5-FU and folinic acid have been shown to be a safe and effective chemotherapeutic backbone in patients with cholangiocarcinoma but also in other cancers of the gastrointestinal tract such as gastric and colorectal cancer. Irinotecan is widely and regularly used in patients with gastric and colorectal cancer but also in patients with cholangiocarcinoma and has a favourable safety profile. Typical side effects of irinotecan, 5-FU and folinic acid are hematotoxicity, diarrhea and hand-food-skin reaction (for details see „Fachinformation irinotecan, 5-FU and folinic acid“) which are manageable with supportive therapies and dose reductions. However, there has been no evidence from prospective randomized trials that the addition of irinotecan to 5-FU and folinic acid improves the outcome of patients suffering from cholangiocarcinoma. Due to its favourable toxicity profile and its evident potency proven in several trials in patients with gastric and colorectal cancer the addition of irinotecan to 5-FU and folinic acid is expected to improve the overall survival of patients with cholangiocarcinoma with only modest increase of toxicity.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Aug 2017
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Germany: 27
|
||
Worldwide total number of subjects |
27
|
||
EEA total number of subjects |
27
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
9
|
||
From 65 to 84 years |
18
|
||
85 years and over |
0
|
||
|
||||||||||
|
Recruitment
|
||||||||||
Recruitment details |
First patient in: August 2017 Last patient in: February 2024 Therapy duration: 12 months Follow-up duration: every 6 weeks after EOT until death 56 patients (2:1 randomisation) were planned. In Amendment V3.0, the sample size was changed to 23 patients treated with FOLFIRI. Arm B was closed | |||||||||
|
Pre-assignment
|
||||||||||
Screening details |
The screening period is the time preceding enrollment and includes the 28-day period for performing screening assessments. 32 patients were screened, 5 patients were screening failures due to laboratory reasons or patients unwillingness to participate in the trial. | |||||||||
|
Period 1
|
||||||||||
Period 1 title |
overall trial (overall period)
|
|||||||||
Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
|
|||||||||
Blinding used |
Not blinded | |||||||||
Blinding implementation details |
Not applicable
|
|||||||||
|
Arms
|
||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||
|
Arm title
|
Arm A | |||||||||
Arm description |
FOLFIRI Arm (5-Fluoruracil, Folinic Acid, Irinocetan) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
IRINOTECAN
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Concentrate for solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
Dosage and administration details |
Irinotecan is manufactured by Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg vor der Höhe and other pharmaceutical companies. It is produced in a dosage of 20 mg/mL in vials of 2 mL, 5 mL, 15, and 25 mL. It will be administered in a dosage of 180 mg/m2 over 1,5h after intravenous infusion of supportive medication including a 5-HT3 receptor antagonist and 8mg dexamethasone. Irinotecan vials contain 20 mg/mL irinotecan and sorbitol, lactic acid, sodium hydroxide, hydrochlorid acid. Irinotecan must be diluted in a 250 mL bag containing 5 % glucose or 0.9 % sodium chloride.
|
|||||||||
Investigational medicinal product name |
5-Fluorouracil
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Concentrate for solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
Dosage and administration details |
5-FU is a generic drug which is manufactured by Medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany and other companies. It is produced in vials with a dosage of 50 mg/ml. It will administered together with oncofolic 400 mg/m2 body surface in a dosage of 2000 mg/m2 body surface over 48h in a self portable elastomeric infusion system (e.g. Baxter infusor) in an outpatient setting after intravenous infusion of supportive drugs including such as granisetron or ondasetron and dexamethasone 8mg. Infusion via a port system is mandatory. Patients in arm A (FOLFIRI) receive an intravenous infusion of 180 mg/m2 irinotecan over 1,5h before 5-FU/oncofolic administration.
5-FU can be ordered in bottles of 5 to 200 mL. 5-FU bottles contain 5-FU 50mg/m2 and sodium hydroxid and water for injection. It is a colorless or pale yellow solution. 5-FU may only be dissolved in 0.9 % sodium chloride or in 5 % glucose
|
|||||||||
Investigational medicinal product name |
Folinic Acid
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Concentrate and solvent for solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
Dosage and administration details |
Folinic acid is manufactured by Medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany. It will be administered in both treatment arms in dosage of 400mg/m2 body surface in combination with 5-FU 2000 mg/m2 body surface over 48h in a self portable elastomeric infusion system (e.g. Baxter infusor). Folinic acid can be ordered in vials of 2-18 mL containing 54.65 mg/ml Folinic acid disodium salt, corresponding to 50 mg/ml Folinic acid.
|
|||||||||
|
Arm title
|
Arm B | |||||||||
Arm description |
5-Fluorouracil (5-FU), Folinic Acid | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
5-Fluorouracil
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Concentrate for solution for infusion
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
Dosage and administration details |
5-FU is a generic drug which is manufactured by Medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany and other companies. It is produced in vials with a dosage of 50 mg/ml. It will administered together with oncofolic 400 mg/m2 body surface in a dosage of 2000 mg/m2 body surface over 48h in a self portable elastomeric infusion system (e.g. Baxter infusor) in an outpatient setting after intravenous infusion of supportive drugs including such as granisetron or ondasetron and dexamethasone 8mg. Infusion via a port system is mandatory. Patients in arm A (FOLFIRI) receive an intravenous infusion of 180 mg/m2 irinotecan over 1,5h before 5-FU/oncofolic administration.
5-FU can be ordered in bottles of 5 to 200 mL. 5-FU bottles contain 5-FU 50mg/m2 and sodium hydroxid and water for injection. It is a colorless or pale yellow solution. 5-FU may only be dissolved in 0.9 % sodium chloride or in 5 % glucose.
|
|||||||||
Investigational medicinal product name |
Folinic Acid
|
|||||||||
Investigational medicinal product code |
||||||||||
Other name |
||||||||||
Pharmaceutical forms |
Concentrate for solution for injection
|
|||||||||
Routes of administration |
Infusion
|
|||||||||
Dosage and administration details |
Folinic acid is manufactured by Medac, Gesellschaft für klinische Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany. It will be administered in both treatment arms in dosage of 400mg/m2 body surface in combination with 5-FU 2000 mg/m2 body surface over 48h in a self portable elastomeric infusion system (e.g. Baxter infusor). Folinic acid can be ordered in vials of 2-18 mL containing 54.65 mg/ml Folinic acid disodium salt, corresponding to 50 mg/ml Folinic acid. It is a colorless or pale yellow solution. Folinic acid should be stored at 2-8°C until mixture with 5-FU. After mixture with 5-FU or dilution in 0.9% sodium chloride it is stable for 72 h at 20-25°C.
|
|||||||||
|
||||||||||
|
||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
||||||||||||||||||||||||||||||||||||||||
Reporting group title |
overall trial
|
|||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Arm A
|
||
Reporting group description |
FOLFIRI Arm (5-Fluoruracil, Folinic Acid, Irinocetan) | ||
Reporting group title |
Arm B
|
||
Reporting group description |
5-Fluorouracil (5-FU), Folinic Acid | ||
|
|||||||||||||
End point title |
Determination of the progression free survival (PFS) | ||||||||||||
End point description |
Note that because of low recruiting, the primary aim was changed in the last protocol version where Arm B (control) was stopped. While the original primary aim was the comparison between the two treatment arms with the logrank test (p=0.304), the updated primary aim was to prove that median PFS was at least 2 months in Arm A (FOLFIRI) with a one-sided test and significance level of alpha=10%. Table 10 already shows that the two-sided confidence interval of median PFS in Arm A (FOLFIRI) was 2.2 to 14.5 months and, therefore, completely above the reference value of 2 months. The one-sided test gives a p-value of p<0.0001 and the primary aim could be successfully proved.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
from start to tumor progression
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Activity analysis | ||||||||||||
Statistical analysis description |
Standard descriptive methods will be used to present all relevant data.
Continuous data will be summarized with the following items: frequency, median, range and mean and standard deviation.
Quantitative data during study course (during treatment and/or follow up) are summarized as mean or medium, minimum and maximum value observed in each patient during the observation time course and illustrated by individual curves.
Categorical data will be presented in with frequencies and percentages of
|
||||||||||||
Comparison groups |
Arm A v Arm B
|
||||||||||||
Number of subjects included in analysis |
27
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other [1] | ||||||||||||
Method |
|||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||
Point estimate |
2
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
0.1 | ||||||||||||
upper limit |
- | ||||||||||||
| Notes [1] - ITT analysis |
|||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
treatment period
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
all patients
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
04 Feb 2020 |
Clarificatin of end of study |
||
01 Mar 2021 |
Number of FOLFIRI treated patients was reduced to 23 patients and arm B (5-FU/folinic acid) was closed. |
||
24 Nov 2021 |
Protocol and informed consent form were adapted due to change of PI from Prof. Oliver Waidmann to Prof. Fabian Finkelmeier. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
