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    Clinical Trial Results:
    A multi-center, randomized, open-label, mechanism of action trial on the biological effects of the therapeutic cancer vaccine Stimuvax® (L-BLP25) in rectal cancer subjects undergoing neoadjuvant chemoradiotherapy.

    Summary
    EudraCT number
    		 2011-000847-25
    Trial protocol
    		 BE   PT   DE   NL   AT  
    Global end of trial date
    12 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EMR 63325-013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01507103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    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
    12 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this mechanistic study is to determine the impact of L-BLP25 vaccine on the mucinous glycoprotein 1 - (MUC1) specific immune response in patients with newly diagnosed rectal cancer who are eligible for neoadjuvant therapy. L-BLP25 is designed to induce an immune response that may lead to immune rejection of tumor tissues that aberrantly express MUC1 antigen. MUC1 is highly expressed in all colorectal cancers and since the adaptive immune system plays a role in the prognosis of rectal cancer, it is reasonable to speculate that the vaccination with L BLP25 might boost the tumor-specific response and increase the number of TILs.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Portugal: 23
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 43
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    81
    From 65 to 84 years
    42
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First/last subject (informed consent): Feb 2012/Dec 2013. Study completion date: Jun 2014.

    Pre-assignment
    Screening details
    		 Enrolled: 140 screened for eligibility; 16 subjects were not randomized due to non-fulfillment of inclusion or exclusion criteria and 124 subjects were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA
    Arm description
    		 Single dose of cyclophosphamide 300 milligram per square meter [mg/m^2] to a maximum of 600 milligram [mg]) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 microgram [mcg]) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chemoradiotherapy (Radiotherapy+Captecitabine or -Fluorouracil)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Not mentioned , Oral use
    Dosage and administration details
    Radiotherapy of 45-52 grays (Gy) was applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-fluorouracil (5-FU) was administered orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Investigational medicinal product name
    Tecemotide (L-BLP25)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 8 consecutive weekly subcutaneous vaccinations with 806 mcg of tecemotide at Weeks 1, 2, 3, 4, 5, 6, 7 and 8, concomitantly with the chemoradiotherapy, followed by a 9th subcutaneous injection 7 to 11 days prior to surgery.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single intravenous infusion of 300 mg/m^2 (to a maximum 600 mg) of CPA was given 3 days before the first tecemotide (L-BLP25) administration.

    Arm title
    		 Chemoradiotherapy+Tecemotide (L-BLP25)
    Arm description
    		 Weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tecemotide (L-BLP25)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received 8 consecutive weekly subcutaneous vaccinations with 806 mcg of tecemotide (L-BLP25) at Weeks 1, 2, 3, 4, 5, 6, 7 and 8, concomitantly with the chemoradiotherapy, followed by a 9th subcutaneous injection 7 to 11 days prior to surgery.

    Investigational medicinal product name
    Chemoradiotherapy (Radiotherapy+Captecitabine or -Fluorouracil)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Not mentioned
    Dosage and administration details
    Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Arm title
    		 Chemoradiotherapy
    Arm description
    		 Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Chemoradiotherapy (Radiotherapy+Captecitabine or -Fluorouracil)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor, solution
    Routes of administration
    Not mentioned
    Dosage and administration details
    Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Number of subjects in period 1 [1]
    		Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Started
    39
    41
    42
    Completed
    39
    41
    42
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline characteristics are reported for safety analysis set which included all the subjects who received at least one dose of study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA
    Reporting group description
    		 Single dose of cyclophosphamide 300 milligram per square meter [mg/m^2] to a maximum of 600 milligram [mg]) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 microgram [mcg]) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Reporting group title
    Chemoradiotherapy+Tecemotide (L-BLP25)
    Reporting group description
    		 Weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Reporting group title
    Chemoradiotherapy
    Reporting group description
    		 Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Reporting group values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy Total
    Number of subjects
    		 39 41 42 122
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ( 10.74 ) 62.2 ( 10.12 ) 60.3 ( 8.77 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 14 10 33
        Male
    		 30 27 32 89

    End points

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    End points reporting groups
    Reporting group title
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA
    Reporting group description
    		 Single dose of cyclophosphamide 300 milligram per square meter [mg/m^2] to a maximum of 600 milligram [mg]) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 microgram [mcg]) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Reporting group title
    Chemoradiotherapy+Tecemotide (L-BLP25)
    Reporting group description
    		 Weekly subcutaneous vaccinations with tecemotide (L-BLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Reporting group title
    Chemoradiotherapy
    Reporting group description
    		 Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5-FU will be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Primary: Change from baseline in tumor immune response evaluated by immunohistochemical (IHC) analysis of tumor infiltrating lymphocytes (TILs) at week 14 (post-surgery)

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    End point title
    		 Change from baseline in tumor immune response evaluated by immunohistochemical (IHC) analysis of tumor infiltrating lymphocytes (TILs) at week 14 (post-surgery)
    End point description
    Tumor biopsy samples were collected prior to baseline and after the surgery. The TILs were evaluated in 3 of the most abundant high-power fields (x40) per sample and the mean value considered (after excluding the lowest and the highest value). The tumor immune response was calculated as number of TILs divided by 100 tumor cells. This endpoint was assessed in immunomonitoring analysis set which included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing were available and whose tumor biopsy at baseline was MUC1-positive. Within the data table, n=number of subjects analyzed for each category.
    End point type
    Primary
    End point timeframe
    Baseline and Week 14 (post-surgery)
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    27
    33
    30
    Units: per 100 tumor cells
    arithmetic mean (standard deviation)
        CD8+ (n=23, 27, 26)
    0.609 ( 5.4241 )
    0.543 ( 4.5009 )
    1.538 ( 3.9509 )
        CD8+/GrB+ (n=23, 27, 26)
    0.565 ( 3.1646 )
    0.216 ( 2.4187 )
    0.936 ( 2.7649 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an analysis of covariance (ANCOVA) model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.794 [1]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.65
    Notes
    [1] - Arm effect
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25) v Chemoradiotherapy
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.794 [2]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 0.43
    Notes
    [2] - Arm effect
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Category: CD8+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy+Tecemotide (L-BLP25)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.794 [3]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.82
    Notes
    [3] - Arm effect
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.654 [4]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 0.57
    Notes
    [4] - Arm effect
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25) v Chemoradiotherapy
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.654 [5]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 0.31
    Notes
    [5] - Arm effect
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Category: CD8+/GrB+ The difference between baseline and surgical tumor samples was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value as covariate. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy+Tecemotide (L-BLP25)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.654 [6]
    Method
    		 type III SS F-test
    Parameter type
    		 Effect estimate
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 0.74
    Notes
    [6] - Arm effect

    Primary: Immunological response to treatment in relation to microsatellite instability (MSI) status: number of subjects per MSI category

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    End point title
    		 Immunological response to treatment in relation to microsatellite instability (MSI) status: number of subjects per MSI category
    End point description
    A potential association between MSI status (present or absent) and the primary endpoints (difference from baseline to surgery in CD8+ and CD8+/GrB+ T cell infiltration) was evaluated. This endpoint was assessed in immunomonitoring analysis set which included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing were available and whose tumor biopsy at baseline was MUC1-positive.
    End point type
    Primary
    End point timeframe
    18 weeks
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    27
    33
    30
    Units: Subjects
        No
    25
    32
    30
        Yes
    2
    1
    0
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy v Chemoradiotherapy+Tecemotide (L-BLP25)+CPA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.921
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 0.67
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25) v Chemoradiotherapy
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.921
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 0.44
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Category: CD8+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline = Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy+Tecemotide (L-BLP25)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.921
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.83
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Category:CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm C) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy v Chemoradiotherapy+Tecemotide (L-BLP25)+CPA
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.89
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.58
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Category: CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm B vs Arm C) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25) v Chemoradiotherapy
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.89
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.31
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Category: CD8+/GrB+ The difference in T cell infiltration from baseline to surgery was analysed and compared across the 3 treatment arms (effect estimate for Arm A vs Arm B) based on an ANCOVA model. Difference from baseline=Surgery value-Baseline value. Adjustment was based on ANCOVA model with treatment arm as factor and baseline value and MSI category as covariates. No interaction included. Pairwise tests have been performed to compare Arm A with Arm C, Arm B with Arm C, and Arm A with Arm B.
    Comparison groups
    Chemoradiotherapy+Tecemotide (L-BLP25)+CPA v Chemoradiotherapy+Tecemotide (L-BLP25)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.89
    Method
    		 type III SS F-test
    Parameter type
    		 Estimate
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.74

    Primary: Change from baseline in interferon (IFN)-gamma secretion of mononuclear cells in response to MUC-1 by enzyme-linked immunosorbent spot (ELISpot) at post-baseline

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    End point title
    		 Change from baseline in interferon (IFN)-gamma secretion of mononuclear cells in response to MUC-1 by enzyme-linked immunosorbent spot (ELISpot) at post-baseline [7]
    End point description
    IFN-gamma secretion of mononuclear cells in response to MUC1 was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline.
    End point type
    Primary
    End point timeframe
    Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial)
    Notes
    [7] - 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: Data was not analyzed as no acceptable ELISpot assay was available.
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Subjects
    Notes
    [8] - Data were not analyzed as no acceptable ELISpot assay was available.
    [9] - Data were not analyzed as no acceptable ELISpot assay was available.
    [10] - Data were not analyzed as no acceptable ELISpot assay was available.
    No statistical analyses for this end point

    Primary: Change from baseline in IFN-gamma secretion of mononuclear cells in response to carcinoembryonic antigen (CEA) by ELISpot at post-baseline

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    End point title
    		 Change from baseline in IFN-gamma secretion of mononuclear cells in response to carcinoembryonic antigen (CEA) by ELISpot at post-baseline [11]
    End point description
    IFN-gamma secretion of mononuclear cells in response to CEA was to be measured by ELISpot. The maximal post-baseline value out of Week 5, Week 11-13 (pre-surgery), and Week 16-18 (follow-up / end-of trial) was evaluated in comparison to Baseline.
    End point type
    Primary
    End point timeframe
    Baseline, Week 5, Week 13 (pre-surgery), and Week 18 (end-of trial)
    Notes
    [11] - 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: Data was not analyzed as no acceptable ELISpot assay was available.
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    Units: Subjects
    Notes
    [12] - Data were not analyzed as no acceptable ELISpot assay was available.
    [13] - Data were not analyzed as no acceptable ELISpot assay was available.
    [14] - Data were not analyzed as no acceptable ELISpot assay was available.
    No statistical analyses for this end point

    Secondary: Change from baseline in peritumoral immune response at week 14 (post-surgery)

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    End point title
    		 Change from baseline in peritumoral immune response at week 14 (post-surgery)
    End point description
    Ki67+CD3+ T cells; regulatory T cells (FOXP3+) and myeloid-derived suppressor cells (CD33+CD14-); other immune cells such as NK cells (CD3-CD57+), B cells (CD20+), macrophages (CD68+), and dendritic cells (S100+). Peritumoral immune response was calculated as number of lymphoid cells at the margin of the tumor or in the tumor bed (if there is complete pathological response). The number "99999" in the arithmetic mean and standard deviation indicate that no parameters were identified with a p-value less than (<) 0.05 for either arm or interaction effect. Thus, no summary statistics are provided for the difference from baseline in IHC parameters for the immunomonitoring analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 14 (post-surgery)
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    27
    33
    30
    Units: mg/mL
        arithmetic mean (standard deviation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change from baseline in immunological response in peripheral blood at week 18 (follow-up / end-of trial)

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    End point title
    		 Change from baseline in immunological response in peripheral blood at week 18 (follow-up / end-of trial)
    End point description
    Immunological changes in peripheral blood were evaluated based on fluorescence analysis cell sorter phenotypic characterization of T cells (CD3+CD4+ and CD3+CD8+) and of markers of activation and proliferation (CD27, BTLA); and regulatory cells such as CD3+CD4+ (or CD8+) CD45RA+CD25+FoxP3+CD127 T cells. Immunological Response in peripheral blood was measured on a continuous scale. This endpoint was assessed in immunomonitoring analysis set which included all subjects for whom at least the baseline ELISpot blood and tumor sample, tumor sample at surgery and pre-surgery ELISpot blood drawing were available and whose tumor biopsy at baseline was MUC1-positive. Within the data table, n=number of subjects analysed for each category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 18 (follow-up / end-of trial)
    End point values
    		 Chemoradiotherapy+Tecemotide (L-BLP25)+CPA Chemoradiotherapy+Tecemotide (L-BLP25) Chemoradiotherapy
    Number of subjects analysed
    27
    33
    30
    Units: Log2 (%)
    arithmetic mean (standard deviation)
        CD3-CD56+CD16+GranzymeB+ (n=26,30,24)
    -0.013 ( 0.1051 )
    -0.046 ( 0.1259 )
    -0.081 ( 0.2238 )
        CD3-CD56+CD16+Perforin+ (n=26,30,24)
    -0.05 ( 0.0769 )
    -0.033 ( 0.1868 )
    -0.088 ( 0.2282 )
        CD3+CD4+CD27+ (n=26,30,24)
    -0.181 ( 0.1848 )
    -0.135 ( 0.1521 )
    -0.099 ( 0.1913 )
        CD3-CD56+CD16+Granzyme B+/LY (n=26,30,24)
    0.264 ( 0.5885 )
    0.047 ( 1.2787 )
    0.415 ( 0.604 )
        CD3-CD56+CD16+Perforin+/LY (n=26,30,24)
    0.226 ( 0.5669 )
    0.058 ( 1.2902 )
    0.411 ( 0.6019 )
        CD3-CD56+CD16-CD107a+ (n=26,30,24)
    0.216 ( 1.201 )
    -0.318 ( 1.5863 )
    0.037 ( 1.0191 )
        CD3+CD8+CD127-FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24)
    0.05 ( 0.3933 )
    0.152 ( 0.5386 )
    -0.012 ( 0.5202 )
        CD3+CD56+CD16-Granzyme B+ (n=26,30,24)
    0.479 ( 1.6943 )
    -0.241 ( 0.9628 )
    -0.024 ( 0.6623 )
        CD3-CD56+CD16+/LY (n=26,30,24)
    0.277 ( 0.5448 )
    0.09 ( 1.2968 )
    0.497 ( 0.6119 )
        CD3-CD19+BTLA4+ (n=27,29,23)
    -0.03 ( 0.0489 )
    -0.028 ( 0.055 )
    -0.017 ( 0.0352 )
        Lymphs Tube 2 (n=27,30,25)
    -1.024 ( 0.4392 )
    -0.941 ( 0.608 )
    -0.952 ( 0.4761 )
        CD3+CD56+CD16+CD107a+ (n=26,30,24)
    -1.216 ( 4.5484 )
    1.966 ( 6.6322 )
    -2.752 ( 6.479 )
        CD3+CD4+BTLA4+ (n=26,30,24)
    0.063 ( 1.4413 )
    0.122 ( 0.4833 )
    -0.035 ( 0.4117 )
        Lymphs Tube 3 (n=27,30,25)
    -0.994 ( 0.4545 )
    -0.92 ( 0.5923 )
    -0.936 ( 0.4746 )
        CD3+CD56+CD16+CCR7+ (n=26,30,24)
    -1.341 ( 4.1442 )
    0.541 ( 6.3502 )
    -3.39 ( 5.1877 )
        CD3+CD8+CD127+FoxP3-CD25-CD45RA+CTLA4-(n=27,29,24)
    -0.604 ( 0.8102 )
    -1.062 ( 1.1436 )
    -0.94 ( 1.2678 )
        Background corrected CD3+CD4+IFNg+ (n=21,27,21)
    0.058 ( 0.9767 )
    0.544 ( 0.9521 )
    0.359 ( 1.3187 )
        CD3+CD56+CD16+Granzyme B+/LY (n=26,30,24)
    0.243 ( 0.6969 )
    -0.201 ( 1.0731 )
    0.131 ( 0.7652 )
        CD3+CD56+CD16+Perforin+/LY (n=26,30,24)
    0.24 ( 0.6997 )
    -0.177 ( 0.992 )
    0.101 ( 0.7617 )
        CD3+CD4+CD127+FoxP3-CD45RA-CD25+CTLA4+(n=27,29,24)
    0.711 ( 1.3825 )
    0.674 ( 1.2689 )
    1.035 ( 1.4996 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Date of first signature of informed consent until the End of Trial visit.
    Adverse event reporting additional description
    Treatmentemergent AEs were defined as those that emerged during treatment, having been absent pretreatment, or worsened relative to the pretreatment state, and with onset dates occurring from the first trial treatment until the EndofTrial visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Chemoradiotherapy+Tecemotide (LBLP25)+ CPA
    Reporting group description
    		 Single dose of cyclophosphamide (300 mg/m^2 to a maximum of 600 mg) was administered intravenously, 3 days prior to the start of vaccination, followed by weekly subcutaneous vaccinations with tecemotide (LBLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Reporting group title
    Chemoradiotherapy
    Reporting group description
    		 Radiotherapy of 45-52 Gy will be applied 5 times per week, over a minimum period of 5 weeks. Capecitabine at a dose of 825 mg/m^2, twice daily or equivalent dose of 5FU was be given orally, starting at the first day of radiotherapy and given 5 to 7 days per week during the time of radiotherapy.

    Reporting group title
    Chemoradiotherapy+Tecemotide (LBLP25)
    Reporting group description
    		 Weekly subcutaneous vaccinations with tecemotide (LBLP25) (actual delivered dose was 806 mcg) administered concomitantly with chemotherapy for 8 weeks, followed by a 9th subcutaneous vaccination 7 to 11 days prior to surgery.

    Serious adverse events
    		 Chemoradiotherapy+Tecemotide (LBLP25)+ CPA Chemoradiotherapy Chemoradiotherapy+Tecemotide (LBLP25)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 39 (25.64%)
    12 / 42 (28.57%)
    10 / 41 (24.39%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Peritumoural oedema
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anastomotic leak
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Coccydynia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Chemoradiotherapy+Tecemotide (LBLP25)+ CPA Chemoradiotherapy Chemoradiotherapy+Tecemotide (LBLP25)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 39 (97.44%)
    41 / 42 (97.62%)
    41 / 41 (100.00%)
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences all number
    1
    3
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 39 (23.08%)
    6 / 42 (14.29%)
    7 / 41 (17.07%)
         occurrences all number
    9
    6
    7
    Influenza like illness
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    4
    0
    0
    Chills
         subjects affected / exposed
    4 / 39 (10.26%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences all number
    4
    1
    2
    Fatigue
         subjects affected / exposed
    12 / 39 (30.77%)
    12 / 42 (28.57%)
    9 / 41 (21.95%)
         occurrences all number
    12
    12
    9
    Injection site haematoma
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    1
    Injection site induration
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 42 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    4
    0
    2
    Injection site erythema
         subjects affected / exposed
    3 / 39 (7.69%)
    0 / 42 (0.00%)
    11 / 41 (26.83%)
         occurrences all number
    3
    0
    11
    Injection site nodule
         subjects affected / exposed
    5 / 39 (12.82%)
    0 / 42 (0.00%)
    11 / 41 (26.83%)
         occurrences all number
    5
    0
    11
    Injection site reaction
         subjects affected / exposed
    7 / 39 (17.95%)
    3 / 42 (7.14%)
    7 / 41 (17.07%)
         occurrences all number
    7
    3
    7
    Injection site pain
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    3
    Pyrexia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 42 (4.76%)
    4 / 41 (9.76%)
         occurrences all number
    2
    2
    4
    Anxiety
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 42 (9.52%)
    1 / 41 (2.44%)
         occurrences all number
    1
    4
    1
    Investigations
    Antinuclear antibody increased
         subjects affected / exposed
    4 / 39 (10.26%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    4
    0
    3
    Weight decreased
         subjects affected / exposed
    3 / 39 (7.69%)
    5 / 42 (11.90%)
    2 / 41 (4.88%)
         occurrences all number
    3
    5
    2
    Injury, poisoning and procedural complications
    Procedural nausea
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 42 (7.14%)
    2 / 41 (4.88%)
         occurrences all number
    1
    3
    2
    Procedural pain
         subjects affected / exposed
    8 / 39 (20.51%)
    7 / 42 (16.67%)
    3 / 41 (7.32%)
         occurrences all number
    8
    7
    3
    Radiation skin injury
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 42 (4.76%)
    9 / 41 (21.95%)
         occurrences all number
    2
    2
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    2
    0
    3
    Dysgeusia
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences all number
    3
    1
    2
    Headache
         subjects affected / exposed
    6 / 39 (15.38%)
    4 / 42 (9.52%)
    1 / 41 (2.44%)
         occurrences all number
    6
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 39 (12.82%)
    6 / 42 (14.29%)
    4 / 41 (9.76%)
         occurrences all number
    5
    6
    4
    Thrombocytopenia
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 42 (9.52%)
    0 / 41 (0.00%)
         occurrences all number
    1
    4
    0
    Leukopenia
         subjects affected / exposed
    4 / 39 (10.26%)
    5 / 42 (11.90%)
    5 / 41 (12.20%)
         occurrences all number
    4
    5
    5
    Neutropenia
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 42 (4.76%)
    1 / 41 (2.44%)
         occurrences all number
    2
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 42 (7.14%)
    3 / 41 (7.32%)
         occurrences all number
    1
    3
    3
    Abdominal pain
         subjects affected / exposed
    5 / 39 (12.82%)
    8 / 42 (19.05%)
    8 / 41 (19.51%)
         occurrences all number
    5
    8
    8
    Abdominal pain upper
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    5 / 41 (12.20%)
         occurrences all number
    2
    0
    5
    Anorectal discomfort
         subjects affected / exposed
    5 / 39 (12.82%)
    7 / 42 (16.67%)
    3 / 41 (7.32%)
         occurrences all number
    5
    7
    3
    Defaecation urgency
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    1
    Constipation
         subjects affected / exposed
    6 / 39 (15.38%)
    7 / 42 (16.67%)
    4 / 41 (9.76%)
         occurrences all number
    6
    7
    4
    Diarrhoea
         subjects affected / exposed
    15 / 39 (38.46%)
    21 / 42 (50.00%)
    18 / 41 (43.90%)
         occurrences all number
    15
    21
    18
    Dyspepsia
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 42 (7.14%)
    1 / 41 (2.44%)
         occurrences all number
    2
    3
    1
    Flatulence
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 42 (7.14%)
    3 / 41 (7.32%)
         occurrences all number
    2
    3
    3
    Gastrointestinal pain
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    0
    Faecal incontinence
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    1
    Nausea
         subjects affected / exposed
    8 / 39 (20.51%)
    13 / 42 (30.95%)
    12 / 41 (29.27%)
         occurrences all number
    8
    13
    12
    Painful defaecation
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 42 (9.52%)
    1 / 41 (2.44%)
         occurrences all number
    3
    4
    1
    Rectal tenesmus
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    2
    0
    2
    Proctalgia
         subjects affected / exposed
    10 / 39 (25.64%)
    12 / 42 (28.57%)
    14 / 41 (34.15%)
         occurrences all number
    10
    12
    14
    Rectal haemorrhage
         subjects affected / exposed
    5 / 39 (12.82%)
    4 / 42 (9.52%)
    2 / 41 (4.88%)
         occurrences all number
    5
    4
    2
    Toothache
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 42 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    1
    0
    3
    Vomiting
         subjects affected / exposed
    6 / 39 (15.38%)
    2 / 42 (4.76%)
    4 / 41 (9.76%)
         occurrences all number
    6
    2
    4
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences all number
    2
    1
    2
    Erythema
         subjects affected / exposed
    5 / 39 (12.82%)
    1 / 42 (2.38%)
    5 / 41 (12.20%)
         occurrences all number
    5
    1
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 42 (7.14%)
    4 / 41 (9.76%)
         occurrences all number
    3
    3
    4
    Rash
         subjects affected / exposed
    5 / 39 (12.82%)
    0 / 42 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    5
    0
    4
    Pruritus
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 42 (2.38%)
    5 / 41 (12.20%)
         occurrences all number
    3
    1
    5
    Haematuria
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    1
    Dysuria
         subjects affected / exposed
    10 / 39 (25.64%)
    5 / 42 (11.90%)
    8 / 41 (19.51%)
         occurrences all number
    10
    5
    8
    Urinary tract pain
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    2 / 41 (4.88%)
         occurrences all number
    2
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 39 (0.00%)
    4 / 42 (9.52%)
    0 / 41 (0.00%)
         occurrences all number
    0
    4
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 42 (4.76%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 42 (7.14%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 42 (7.14%)
    4 / 41 (9.76%)
         occurrences all number
    2
    3
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 39 (17.95%)
    13 / 42 (30.95%)
    6 / 41 (14.63%)
         occurrences all number
    7
    13
    6
    Hypokalaemia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 42 (2.38%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 39 (5.13%)
    0 / 42 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Nov 2011
    In this amendment, the description of the dose of tecemotide administered under protocol EMR 63325-013 (SPRINT) was corrected from 930 mcg to 806 mcg to more accurately reflect the actual quantity of drug administered to subjects.
    02 Nov 2012
    In this amendment, the definitions of AEs/SAEs associated with disease progression and SAEs related to trial treatment were updated; the acceptable time frames for imaging and tecemotide administration were modified; total blood volume collected for biochemistry and overall was adjusted; list of markers for the biomarker assessments was clarified.

    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.
    Not all efficacy data were analyzed as no acceptable ELISpot assay is available. The Sponsor decided to discontinue the development of tecemotide (L-BLP25) in September 2014.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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