Clinical Trial Results:
Randomisierte Studie
zur Wirksamkeit von FOLFIRI
in Kombination mit Cetuximab vs. Bevacizumab in der Erstlinien-Behandlung des metastasierten kolorektalen Karzinoms
English translation:
Randomised study for efficiency of FOLFIRI in combination with Cetuximab vs. Bevacizumab in first-line-therapy of metastatic colorectal cancer
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Summary
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EudraCT number |
2006-004030-32 |
Trial protocol |
DE AT |
Global end of trial date |
21 Nov 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Sep 2021
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First version publication date |
29 Sep 2021
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Other versions |
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Summary report(s) |
Final Report ACCORDING TO § 42B (2) German Drug Law |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AIOKRK0306
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Klinikum der Universität München - Grosshadern
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Sponsor organisation address |
Marchioninistraße 15, München, Germany, 81377
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Public contact |
Medizinische Klinik III
AG Onkologie, Klinikum der Universität München - Grosshadern, +49 89 4400 0, onkologiestudien@med.uni-muenchen.de
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Scientific contact |
Medizinische Klinik III
AG Onkologie, Klinikum der Universität München - Grosshadern, +49 89 4400 0, onkologiestudien@med.uni-muenchen.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Jul 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Nov 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Nov 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Comparative validation of antitumor efficacy measured by objective remissionrate defined by RECIST-criteria (OR= CR+ PR), assessed within intent-to-treat-collective.
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Protection of trial subjects |
All adverse events (AEs) for each cycle were recorded from the first day of administration of study
medication until the end of treatment. Adverse events, denoted as late toxicities were also recorded every
three months during follow up.
Signs, symptoms or medical conditions/diseases that were already present before a subject obtained
study drug treatment were only recorded as AEs if they worsened during study treatment.
There were 27 preprinted terms for common adverse events that could be ticked off in each treatment cycle
with space to fill in other adverse events than those recorded with the preprinted terms. Other adverse
events were coded by MedDRA preferred terms and assigned to the preprinted terms if appropriate. The
severity of AEs had to be graded according to the NCI CTCAE version 3.0 whenever possible and the
causal relationship to the investigational drugs to be evaluated. An AE was analysed as causally related to
study medication when the AE was evaluated by the investigator as causally related to at least one of the
investigational drugs (5-FU, folinic acid, irinotecan, cetuximab, bevacizumab) administered in the respective
treatment arm.
All recorded adverse events were summarized in frequency counts based on the preprinted terms and
MedDRA preferred terms assigned to other adverse events on patient level. A preprinted term or preferred
term was counted only once per patient. A patient with several grades of a preferred term was counted
once with the highest NCI-CTCAE grade.
In addition, the data of laboratory investigations were analysed.
Data from all patients who received at least one dose of any study drug were included in the safety analyses.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Jan 2007
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
5 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 35
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Country: Number of subjects enrolled |
Germany: 717
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Worldwide total number of subjects |
752
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EEA total number of subjects |
752
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
559
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From 65 to 84 years |
193
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||
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Pre-assignment
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Screening details |
- | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
752 | |||||||||
Number of subjects completed |
752 | |||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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FOLFIRI + Cet | |||||||||
Arm description |
1 cycle consisting of: • FOLFIRI regimen, every 2 weeks Irinotecan 180 mg/m² i.v., 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2 Cetuximab initially 400mg/m² as 120-min infusion, followed by 250 mg/m² i.v. as 60-min infusion each day 1 + 8 | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
||||||||||
Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
180 mg/m² i.v., 30 - 90 min day 1
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Investigational medicinal product name |
Folinic acid (racemic)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1
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Investigational medicinal product name |
5-FU bolus
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Investigational medicinal product code |
||||||||||
Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Injection
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Dosage and administration details |
400 mg/m² bolus day 1
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Investigational medicinal product name |
5-FU
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2
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Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Cetuximab initially 400mg/m² as 120-min infusion, followed by 250 mg/m² i.v. as 60-min infusion each day 1 + 8
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Arm title
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FOLFIRI + Bev | |||||||||
Arm description |
1 cycle consisting of: • FOLFIRI regimen, every 2 weeks Irinotecan 180 mg/m² i.v., 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2 Bevacizumab 5 mg/kg of BW i.v. for 30 to 90* minutes day 1 * The 1st administration is given over a period of 90 min, if tolerated well, the second administration over a period of 60 min and the further administrations over a period of 30 min each Continuation of the treatment until: • the tumor progresses • inacceptable toxicity is observed • confirmed CR is achieved • a status for surgical treatment is achieved • the patient asks to end the treatment • the treating physician decides that the therapy should be withdrawn | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
180 mg/m² i.v., 30 - 90 min day 1
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Investigational medicinal product name |
Irinotecan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
180 mg/m² i.v., 30 - 90 min day 1
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Investigational medicinal product name |
Folinic acid (racemic)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1
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Investigational medicinal product name |
5-FU bolus
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Injection
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Dosage and administration details |
400 mg/m² bolus day 1
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Investigational medicinal product name |
5-FU
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2
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Investigational medicinal product name |
Bevacizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Bevacizumab 5 mg/kg of BW i.v. for 30 to 90* minutes day 1
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
FOLFIRI + Cet
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Reporting group description |
1 cycle consisting of: • FOLFIRI regimen, every 2 weeks Irinotecan 180 mg/m² i.v., 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2 Cetuximab initially 400mg/m² as 120-min infusion, followed by 250 mg/m² i.v. as 60-min infusion each day 1 + 8 | ||
Reporting group title |
FOLFIRI + Bev
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Reporting group description |
1 cycle consisting of: • FOLFIRI regimen, every 2 weeks Irinotecan 180 mg/m² i.v., 30 - 90 min day 1 Folinic acid (racemic) 400 mg/m² i.v., 120 min day 1 5-FU 400 mg/m² bolus day 1 5-FU 2400 mg/m² i.v. over a period of 46 h day 1-2 Bevacizumab 5 mg/kg of BW i.v. for 30 to 90* minutes day 1 * The 1st administration is given over a period of 90 min, if tolerated well, the second administration over a period of 60 min and the further administrations over a period of 30 min each Continuation of the treatment until: • the tumor progresses • inacceptable toxicity is observed • confirmed CR is achieved • a status for surgical treatment is achieved • the patient asks to end the treatment • the treating physician decides that the therapy should be withdrawn | ||
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End point title |
objective response rate (ORR) | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
the number of patients with either complete (CR) or partial response (PR) relative to the total number of subjects in the study population of interest. Only the results from
restaging examinations during study therapy and until 28 days after the end.
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Statistical analysis title |
Efficacy Results to SAF Dataset | ||||||||||||
Statistical analysis description |
1-sided Fisher’s exact test and alpha = 0.025
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Comparison groups |
FOLFIRI + Cet v FOLFIRI + Bev
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Number of subjects included in analysis |
593
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.192 [1] | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.17
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.84 | ||||||||||||
upper limit |
1.63 | ||||||||||||
Variability estimate |
Standard error of the mean
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| Notes [1] - Thus, the primary endpoint was not reached and the ORR was not improved in patients treated with FOLFIRI plus cetuximab. |
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End point title |
progression free survival (PFS) | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
PFS was defined as the time from randomisation until first occurrence of PD or death, whichever occurred
first. Subjects alive and without progression at the last date of assessment were censored.
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Statistical analysis title |
KRAS-wild-type patients, SAF | |||||||||||||||
Comparison groups |
FOLFIRI + Cet v FOLFIRI + Bev
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Number of subjects included in analysis |
400
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | |||||||||||||||
P-value |
= 0.46 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
1.06
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.9 | |||||||||||||||
upper limit |
1.26 | |||||||||||||||
Variability estimate |
Standard deviation
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End point title |
overall survival | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
OS was defined as the time from randomisation to the date of death of any cause. Subjects who were alive
at the date of the last assessment were censored.
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Statistical analysis title |
KRAS-wild-type patients, SAF | |||||||||||||||
Comparison groups |
FOLFIRI + Cet v FOLFIRI + Bev
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Number of subjects included in analysis |
400
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | |||||||||||||||
P-value |
= 0.05 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
0.84
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.706 | |||||||||||||||
upper limit |
1.001 | |||||||||||||||
Variability estimate |
Standard deviation
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End point title |
Time to failure of strategy of the first-line treatment | |||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
TFS was defined as the duration from randomisation to the date of death or start of a new systemic
anticancer therapy that contained a substance not included in the study therapy (start of second-line
therapy).
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Statistical analysis title |
Time to failure of strategy of the first-line trea | |||||||||||||||
Comparison groups |
FOLFIRI + Cet v FOLFIRI + Bev
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Number of subjects included in analysis |
400
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | |||||||||||||||
P-value |
= 0.42 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Hazard ratio (HR) | |||||||||||||||
Point estimate |
1.07
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.91 | |||||||||||||||
upper limit |
1.27 | |||||||||||||||
Variability estimate |
Standard deviation
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Adverse events information
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Timeframe for reporting adverse events |
All adverse events (AEs) for each cycle were recorded from the first day of administration of study
medication until the end of treatment. Adverse events, denoted as late toxicities were also recorded every
three months during follow up.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
13.1
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Reporting groups
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Reporting group title |
adverse events according to SAF
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Apr 2007 |
After authorization of cetuximab (Erbitux®) as 5 mg/ml solution for infusion by the European Medicines Agency (EMA) (Doc.Ref. EMEA/CHMP/280402/2008) cetuximab was provided as 5 mg/ml solution for the trial instead of the previously used 2 mg/ml solution that had been used initially. |
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03 Sep 2008 |
• Trials had shown that patients with mutated KRAS did not respond to anti EGFR
treatment. Treatment with cetuximab was to be confined to KRAS-wildtype
patients. Thus the in- and exclusion criteria were amended accordingly to include
only patients with KRAS wild-type. Patients with mutated KRAS had to
discontinue treatment with cetuximab.
• The planned primary statistical analysis was modified to take into account only
patients with KRAS wild-type disease, whereas already included patients with
mutated KRAS status would be analysed only by means of descriptive analyses.
The sample size was increased from 147 to 284 evaluable patients per treatment
arm.
• Also, all subsequently as well as prior obtained tumour samples were to be
analysed regarding the KRAS mutation status.
• A variation for the cetuximab (Erbitux®) marketing authorization was authorized
(Doc.Ref. EMEA/CHMP/280402/2008) in 2008.
Additional indication of cetuximab: treatment of patients with epidermal growth
factor receptor (EGFR) - expressing, KRAS wild-type metastatic colorectal cancer
in combination with chemotherapy.
Therefore cetuximab was no longer supplied as study medication, but had to be
prescribed.
• Additional collection of copies of CT images for planned independent review at a
later time point. |
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25 Jan 2011 |
• Addition of a translational research project to search for predictors for response to
cetuximab and bevacizumab in the treatment of mCRC patients. Pharmacogenetic
factors were to be analysed in an additionally collected blood sample.
• The accountability of the biostatistics and data management services were
transferred from „Wissenschaftlicher Service Pharma (WiSP) GmbH“ to
„ClinAssess GmbH“. |
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20 Apr 2012 |
• Two secondary endpoints were added:
- Time to failure of strategy“ (TFS) for first-line treatment
- Depth of remission (maximum percentage decrease of tumour size compared to
baseline tumour size).
Planned statistical analysis of the secondary endpoints was added.
• From the updated SmPCs new information regarding safety was introduced for
FOLFIRI, cetuximab and bevacizumab.
• An independent radiological review for the evaluation of tumour response was
established. Tumour response in the independent review was to be evaluated
according to RECIST 1.1 (in contrast to local assessment of tumour response with
RECIST 1.0)
• K-RAS genotyping had revealed a proportion of 144 patients with mutated or
unknown K-RAS genotype (patients included before Amendment 2) and actual
data to the number of drop outs were evaluable.
Thus, the number of patients was increased to 800 patients overall, to obtain the
required 256 evaluable KRAS wild-type patients per treatment arm.
• Duration of patient recruitment time was extended from 48 to 72 months. |
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19 Apr 2013 |
• Change from trial phase II to trial phase III according to the number of recruited
patients |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25088940 |
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