Clinical Trial Results:
Phase II Clinical Study of Cetuximab in Refractory Colorectal Cancer With K-RAS Mutated and Favourable FcγR IIa (CD32) Genotype
Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
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Summary
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EudraCT number |
2010-023580-18 |
Trial protocol |
ES |
Global end of trial date |
10 Dec 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Jul 2016
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First version publication date |
28 Jul 2016
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Other versions |
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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 |
EMR 062202-529
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01450319 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merck KGaA
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Sponsor organisation address |
Frankfurter Strasse 250, Darmstadt, Germany, 64293
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Public contact |
Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
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Scientific contact |
Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
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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 |
10 Dec 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
10 Dec 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Dec 2014
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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 |
This national, multicenter, open-label phase 2 study without any control arm aims to evaluate the activity of cetuximab monotherapy in the treatment of refractory colorectal cancer in subjects with K-RAS mutated and FcγRIIa polymorphism tumors, in which there is no therapeutic alternative for treatment. Failure of the first and second line conventional therapeutic lines was documented.
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Protection of trial subjects |
Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Dec 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
12 Months | ||
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 |
Spain: 70
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Worldwide total number of subjects |
70
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EEA total number of subjects |
70
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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) |
36
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From 65 to 84 years |
34
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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 |
A total of 73 patients were enrolled in the screening for the trial. Three patients were excluded from the modified intent-to-treat (MITT) because they did not receive any dose of the study drug. | ||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
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Arms
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Arm title
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Cetuximab | ||||||
Arm description |
Cetuximab was administered intravenously every 2 weeks until disease progression, death, or consent withdrawal. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Cetuximab
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Investigational medicinal product code |
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Other name |
Erbitux
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cetuximab was administered at a dose of 500 milligram per square meter (mg/m^2) every 2 weeks until disease progression, death, or consent withdrawal.
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Baseline characteristics reporting groups
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Reporting group title |
Cetuximab
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Reporting group description |
Cetuximab was administered intravenously every 2 weeks until disease progression, death, or consent withdrawal. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cetuximab
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Reporting group description |
Cetuximab was administered intravenously every 2 weeks until disease progression, death, or consent withdrawal. | ||
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End point title |
Overall Survival (OS) time [1] | ||||||||
End point description |
Overall survival was defined as the time from date of informed consent signature until death. Modified intent-to-treat (MITT) analysis set included all the subjects who received study drug treatment.
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End point type |
Primary
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End point timeframe |
From the date of informed consent signature until death, assessed up to 3 years
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The one-sided null hypothesis H0: Median ≤ 5 months was pre-specified and was to be tested at a significance level of 0.025. H0 was rejected, because the lower boundary of the 95%CI of the median OS was 5.42 and thus the median OS presented is statistically significant greater than 5 months. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of subjects with Disease control rate (DCR) | ||||||||
End point description |
DCR was defined as those subjects achieving complete response (CR), partial response (PR) or stable disease (SD), according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). For target lesions (TLs), CR was defined as disappearance of all TLs; PR was defined as at least a 30 percent (%) decrease in sum of longest diameter (SLD) of TLs, taking as a reference the baseline (BL) SLD; Stable disease (SD) was defined as neither sufficient decrease in SLD to qualify for PR nor sufficient increase in SLD to qualify for PD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference smallest SLD recorded since the treatment started. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels; SD was defined as persistence of 1 or more NTLs and/or maintenance of tumor marker levels above normal limits. MITT analysis set included all the subjects who received study drug treatment.
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End point type |
Secondary
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End point timeframe |
From the date of informed consent signature until progressive disease, assessed up to 3 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival (PFS) time | ||||||||
End point description |
PFS was defined as the time from informed consent signature until progressive disease (PD) or death, whatever occurred first. Subjects who did not have disease progression or were lost to follow-up, were censored at the date of last contact, known to be alive and progression free; moreover, those subjects who started a new treatment (different from cetuximab), were censored at the date of starting the new treatment. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from BL or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Subjects without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. MITT analysis set included all the subjects who received study drug treatment.
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End point type |
Secondary
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End point timeframe |
From the date of informed consent signature until progressive disease (PD) or death, assessed up to 3 years
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of subjects with Adverse Events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, AEs leading to death | ||||||||||||||
End point description |
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety analysis set included all the subjects who received at least one dose of the study drug treatment.
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End point type |
Secondary
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End point timeframe |
From the date of enrollment up to 30 days after the last dose of study drug administration, assessed up to 3 years
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of subjects with Fcγ receptors (FCγR) IIa/IIIa polymorphisms | ||||||||||||||||
End point description |
The antibody fragment C portion (FCy) of cetuximab interacts with Fc-gamma receptors (FCyRs) expressed by immune effector cells. Polymorphisms were described in genes coding for FCyRIIa and in FCyRIIIa. A histidine/arginine polymorphism at position 131 for FCyRIIa gene and valine ⁄ phenylalanine polymorphism at position 158 for the FCyRIIIa gene were reported to be functionally relevant in the ADCC mechanism. All subjects were analyzed and classified as carriers of every different polymorphism of FCy Receptors: for FCyRIIa (H/H, homozygous alleles with histidine and R/H, heterozygous alleles with arginine/histidine) and FCyRIIIa (V/V, homozygous alleles with valine, F/F, homozygous alleles with phenylalanine and F/V, heterozygous alleles with valine ⁄ phenylalanine) (units: subjects with every type of polymorphism) .The FCyR genotype was determined using a TaqMan Allelic Discrimination Assay. MITT analysis set included all the subjects who received study drug treatment.
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End point type |
Secondary
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End point timeframe |
Baseline
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Overall Survival (OS) Related to Codon G13D | ||||||||||||
End point description |
OS was defined as the time from informed consent signature until death. Subjects without death were censored at the last date known alive (within the study). MITT analysis set included all the subjects who received study drug treatment. Number of subjects analysed signifies number of evaluable subjects for this endpoint. “n” signifies number of evaluable subjects for each category, as specified. Here "99999" for Confidence interval signifies data not valuated due to lack of events.
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End point type |
Secondary
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End point timeframe |
From the date of informed consent signature until death, lost-to-follow-up or end of study, whatever occurred first (maximal up to 3 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall survival (OS) related to Killer Inhibitory Receptors 2DS4 (KIR2DS4) functional receptor (f/d) and non-functional receptor (NFR) | ||||||||||||
End point description |
OS was defined as the time from informed consent signature until death. Subjects without death were censored at the last date known alive (within the study). MITT analysis set included all the subjects who received study drug treatment. Number of subjects analysed signifies number of evaluable subjects for this endpoint.
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End point type |
Secondary
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End point timeframe |
From the date of informed consent signature until death, lost-to-follow-up or end of study, whatever occurred first (maximal assessed up to 3 years)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Beta 2-microglobulin | ||||||||||||
End point description |
MITT analysis set included all the subjects who received study drug treatment. Number of subjects analysed signifies number of evaluable subjects for this endpoint. “n” signifies number of evaluable subjects for each category, as specified.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 8
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
AEs with onset from the date of enrollment up to 30 days after the last dose of study drug administration; assessed up to 3 years.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Cetuximab
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Reporting group description |
Cetuximab was administered intravenously at a dose of 500 milligram per square meter (mg/m^2) every 2 weeks until disease progression, death, or consent withdrawal. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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Date |
Amendment |
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18 Mar 2011 |
The main protocol change was the modification of inclusion criteria to add a reference to the following treatments: 5-Fluorouracil (5-FU), Capecitabine, Irinotecan, Oxaliplatin or Bevacizumab. |
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10 Apr 2012 |
- The primary objective was changed to OS.
- Some secondary objectives were changed (time to progression [TTP] analysis to objective response rate [ORR] analysis) and new ones (molecular analyses) were added.
- Treatment administration length was changed (from 60 minutes in previous version, to the following schedule: 120 minutes in first cycle followed by 90 minutes for second cycle and 60 minutes for third cycle onwards).
- The inclusion criteria were changed: to eliminate the age upper limit, to include the heterozygous and/or homozygous genotypes in FcγRIIa. However, FcγRIIIa was not included due to the low frequency of the polymorphism, to change the previous cancer treatment requirements (only two chemotherapy lines).
- The sample size was increased, from 55 in previous version, to 70 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 | |||
