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    Clinical Trial Results:
    LICC: L-BLP25 in Patients with Colorectal Carcinoma after curative resection of hepatic metastases – a randomized, placebo-controlled, multicenter, multinational, double blinded phase II trial

    Summary
    EudraCT number
    2011-000218-20
    Trial protocol
    DE   AT   BE  
    Global end of trial date
    24 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Mar 2019
    First version publication date
    06 Mar 2019
    Other versions
    Summary report(s)
    LICC_Synopse_EudraCT_20190124

    Trial information

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    Trial identification
    Sponsor protocol code
    LICC01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01462513
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Mainz University Medical Center
    Sponsor organisation address
    Langenbeckstraße 1, Mainz, Germany, 55131
    Public contact
    Prof. Dr. med. Carl Christoph Schimanski, Klinikum Darmstadt GmbH, +49 (6151) 107 6500, Carl.Schimanski@mail.klinikum-darmstadt.de
    Scientific contact
    Prof. Dr. med. Markus Möhler, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, +49 (613) 613117607, markus.moehler@unimedizin-mainz.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was the comparative evaluation of recurrence-free survival time and three year overall survival between the treatment groups cyclophosphamide + tecemotide (L-BLP25) versus saline + placebo.
    Protection of trial subjects
    The trial was performed in accordance with the ethical principles laid down in the Declaration of Helsinki and are consistent with Good Clinical Practice. The informed consent form (ICF) of patients was obtained prior to study participation in accordance with a) §40 I 3 No. Lit., b) II 1 AMG and § 40 I 3 No. 3 Lit and c) IIa 1&2 AMG. Nature, objective and consequences of the study, possible benefits and disadvantages, risks and the study procedure were explained to each patient orally and in writing. The patients were informed that, by signing the ICF, they permitted authorized representatives of the sponsor and the regulatory authorities to access study-related personal data without violating the confidentiality of the patient. Patients were informed that their consent to access their data might not be revoked. Each patient was given enough time to read and discuss the ICF with the investigator prior to giving written consent. Before entry to the study and prior to the conduct of any study-related procedure, consent was recorded by means of the patient’s dated signature. Each patient was given a copy of the information sheet and his/her signed consent form. Only eligible patients were included into this study. Clinical site monitoring was conducted to ensure that the rights of the subjects were protected. Safety assessments consisted of regular monitoring and recording of (serious) adverse events until 30 days after the end of treatment and regular monitoring of hematology, blood chemistry, vital signs and physical condition during the whole treatment phase, with special attention paid to signs and symptoms that might have indicated an autoimmune disorder. Dose adjustments were not permitted for patients who did not tolerate dosing as per protocol. The trial blind might have been broken in case of an emergency. Epinephrine, antihistamine and hydrocortisone were available in the event of an anaphylactic reaction.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Germany: 119
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    80
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with metastatic colorectal carcinoma, who had undergone complete resection of their primary tumor & recent resection of their liver metastases (R0 or R1) were recruited within 8 weeks after resection with curative intent. Out of 25 centers initiated in GER & AT (BE was dropped) 22 recruited patients after intial EC approval on 27.09.2011.

    Pre-assignment
    Screening details
    Eligible patients were randomized via IVRS to treatment with cyclophosphamide + tecemotide versus saline + placebo (2:1) following the receipt of informed consent, completion of all baseline evaluations, and determination of patient eligibility. The randomization to a treatment arm was performed in a stratified manner by resection status R0 v R1.

    Pre-assignment period milestones
    Number of subjects started
    133 [1]
    Intermediate milestone: Number of subjects
    Randomization: 121
    Number of subjects completed
    121

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Patients who did not meet entry criteria: 9
    Reason: Number of subjects
    Duplicate randomization: 1
    Reason: Number of subjects
    Patients who declined participation: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 133 patients screened, 9 patients did not meet the selection criteria for study entry and 2 patients declined participation. One patient was randomized twice. The first randomization of this patient was excluded from analysis. A total of 121 patients were randomized into the study, 79 (65.3%) patients to the tecemotide arm and 42 (34.7%) patients to the placebo arm.
    Period 1
    Period 1 title
    LICC - Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Medication for primary- and maintenance treatments with tecemotide or placebo were packaged identically. Traceability of content was ensured by the combination of kit- batch- and medication-number. Cyclophosphamide or saline infusions were prepared by an unblinded pharmacist; to prevent unblinding of investigators a volume of saline solution corresponding to the calculated volume of cyclophosphamide solution was withdrawn from the infusion bag, so that both infusions had the same volume.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A - tecemotide + cyclophosphamide (ITT population)
    Arm description
    Subjects represented in Arm A received a single iv infusion of 300 mg/m2 (to a maximum of 600 mg) cyclophosphamide 3 days prior to the first tecemotide treatment. Subjects then received 8 consecutive subcutaneous treatments with 930 µg tecemotide at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment (930 µg tecemotide) at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.
    Arm type
    Investigational

    Investigational medicinal product name
    Tecemotide
    Investigational medicinal product code
    L-BLP25
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The IMP (tecemotide) was supplied as a lyophilized powder and stored at 2-8°C. Prior to administration, the powder was reconstituted with sterile 0.9% sodium chloride solution. One vial of the IMP provided drug material for the preparation of a 0.50 mL injection aliquot. The total treatment dose was prepared from four vials of the product. Per each treatment, four 0.50 mL injections were administered to the patient by subcutaneous application at four different anatomical sites.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Endoxan
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single iv infusion of 300 mg/m2 of cyclophosphamide was administered within seven days of randomization and three days (72 hours ± 8 hours) prior to first tecemotide treatment. Cyclophosphamide was dissolved in a 50 mL 0.9 % saline solution prior to administration. A low dose of cyclophosphamide was given with the intention of overcoming tolerance and enhancing any effect of immunotherapy.

    Arm title
    Arm B - placebo + saline - (ITT population)
    Arm description
    Subjects represented in Arm B received a single iv infusion of a volume of saline solution matching the volume of cyclophosphamide solution that would have been given to the subject if he/she were allocated to the verum arm. This was given 3 days prior to the first placebo application. Subjects then received 8 consecutive subcutaneous treatments with placebo at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.
    Arm type
    Control Arm

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The placebo was formulated to provide the same carrier lipid matrix as tecemotide, but without the adjuvant (monophosphoryl lipid A) and BLP25 lipopeptide. Therefore, it should not elicit a MUC1-specific immune response or have an effect on RFS or OS time. A single iv infusion of 0.9% sodium chloride, in the same calculated volume as used for cyclophosphamide dose in the investigational arm, was given to subjects in the control arm within 7 days of randomization and three days (72 hours ± 8 hours) before administering first placebo treatment.

    Number of subjects in period 1
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population)
    Started
    79
    42
    Completed
    65
    40
    Not completed
    14
    2
         Other reason
    2
    -
         Lost to follow-up
    12
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - tecemotide + cyclophosphamide (ITT population)
    Reporting group description
    Subjects represented in Arm A received a single iv infusion of 300 mg/m2 (to a maximum of 600 mg) cyclophosphamide 3 days prior to the first tecemotide treatment. Subjects then received 8 consecutive subcutaneous treatments with 930 µg tecemotide at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment (930 µg tecemotide) at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.

    Reporting group title
    Arm B - placebo + saline - (ITT population)
    Reporting group description
    Subjects represented in Arm B received a single iv infusion of a volume of saline solution matching the volume of cyclophosphamide solution that would have been given to the subject if he/she were allocated to the verum arm. This was given 3 days prior to the first placebo application. Subjects then received 8 consecutive subcutaneous treatments with placebo at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.

    Reporting group values
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population) Total
    Number of subjects
    79 42 121
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    50 30 80
        From 65-84 years
    29 12 41
    Age continuous
    Units: years
        median (full range (min-max))
    60 (24 to 84) 58.5 (30 to 85) -
    Gender categorical
    Units: Subjects
        Female
    30 15 45
        Male
    49 27 76
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    61 24 85
        ECOG 1
    18 18 36
    MUC1 positive staining
    Mucin 1 (MUC1) is an overexpressed glycoprotein in colorectal carcinoma tissue. The expression status was described as an indicator of poor prognosis and a predictor of RFS and OS. The cancer vaccine, tecemotide, composed of liposomes carrying the antigen BLP25 lipopeptide and the adjuvant monophosphoryl lipid A, was expected to trigger an enhanced immune response targeting tumor cells with MUC1 expression. Therefore subgroups of MUC1 expression were formed according to expression levels to elucidate a potential connection between MUC1 expression state and survival outcome.
    Units: Subjects
        Low
    11 5 16
        Moderate
    30 18 48
        Strong
    22 10 32
        Not evaluable
    16 8 24
        Missing
    0 1 1
    Smoking status
    Units: Subjects
        Never
    37 28 65
        Ex
    36 9 45
        Current
    6 5 11
    Alcohol consumption
    Units: Subjects
        Not regularly
    58 35 93
        Regularly
    16 5 21
        Daily
    5 2 7
    TNM: T at first diagnosis
    Units: Subjects
        T1
    4 0 4
        T2
    7 5 12
        T3
    52 30 82
        T4
    13 6 19
        TX
    3 1 4
    TNM: N at first diagnosis
    Units: Subjects
        N0
    21 12 33
        N1
    34 16 50
        N2
    19 12 31
        NX
    5 2 7
    TNM: M at first diagnosis
    Units: Subjects
        M0
    37 8 45
        M1
    37 28 65
        MX
    5 6 11
    Tumor grading at first diagnosis
    Units: Subjects
        G1
    1 1 2
        G2
    61 30 91
        G3
    11 9 20
        G4
    0 1 1
        GX
    6 1 7
    Resection status
    Units: Subjects
        R0
    69 38 107
        R1
    9 4 13
        R2
    1 0 1
    Site of Tumor
    Units: Subjects
        Colon, exact site not known
    9 3 12
        Colon ascending
    7 5 12
        Colon descending
    25 18 43
        Colon multiple sites
    1 0 1
        Colon transversal, exact site not known
    2 1 3
        Colon transversal, proximal
    1 1 2
        Rectum
    34 14 48
    Number of resected metastases
    Units: Subjects
        Number of resections: < 5
    70 34 104
        Number of resections: 5-10
    8 6 14
        Number of resections: > 10
    1 2 3
    BMI at screening
    Units: kg/m²
        median (full range (min-max))
    25.3 (18.3 to 49.6) 24.9 (19.4 to 57.7) -
    Time since first diagnosis
    Units: months
        median (full range (min-max))
    20.0 (1.4 to 121.3) 12.6 (0.9 to 73.6) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A - tecemotide + cyclophosphamide (ITT population)
    Reporting group description
    Subjects represented in Arm A received a single iv infusion of 300 mg/m2 (to a maximum of 600 mg) cyclophosphamide 3 days prior to the first tecemotide treatment. Subjects then received 8 consecutive subcutaneous treatments with 930 µg tecemotide at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment (930 µg tecemotide) at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.

    Reporting group title
    Arm B - placebo + saline - (ITT population)
    Reporting group description
    Subjects represented in Arm B received a single iv infusion of a volume of saline solution matching the volume of cyclophosphamide solution that would have been given to the subject if he/she were allocated to the verum arm. This was given 3 days prior to the first placebo application. Subjects then received 8 consecutive subcutaneous treatments with placebo at weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance treatment at 6-week intervals commencing at week 14, until either recurrence was documented or a treatment period of a total of 2 years was reached. Subjects were discontinued from the study treatment upon recurrence documented by imaging.

    Primary: Recurrence Free Survival (RFS)

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    End point title
    Recurrence Free Survival (RFS)
    End point description
    The RFS was defined as time from date of randomisation until date of recurrence of disease or date of death if no recurrence was documented. RFS was determined by imaging.
    End point type
    Primary
    End point timeframe
    The timeframe for RFS analysis was from date of randomisation until recurrence or death, whichever occured first. Observation of RFS was limited to 36 months from date of randomisation.
    End point values
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population)
    Number of subjects analysed
    79 [1]
    42 [2]
    Units: months
        median (confidence interval 80%)
    6.1 (5.9 to 8.8)
    11.4 (8.6 to 19.8)
    Attachments
    Kaplan-Meier Plot for RFS (ITT)
    Notes
    [1] - 18 patients from arm A were censored for analysis.
    [2] - 14 patients from arm B were censored for analysis.
    Statistical analysis title
    Kaplan-Meier Method
    Statistical analysis description
    Kaplan-Meier method was used for analysis of RFS. Patients were censored if they were declared lost to follow-up, if they withdrew from the study before recurrence or death and if no event was observed during follow-up for recurrence. Recurrence-free time for patients not determined to have a progression of their disease were to be censored as of the date of the last evaluation of recurrence status.
    Comparison groups
    Arm A - tecemotide + cyclophosphamide (ITT population) v Arm B - placebo + saline - (ITT population)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1754 [3]
    Method
    stratified Logrank-Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.338
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.925
         upper limit
    1.97
    Notes
    [3] - A stratified log-rank test with stratification factor resection status was conducted for the difference in RFS distribution.

    Primary: 3-year Overall Survival (OS)

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    End point title
    3-year Overall Survival (OS)
    End point description
    OS is defined as time from randomisation to death from any cause.
    End point type
    Primary
    End point timeframe
    The timeframe for OS analysis was from date of randomisation to death or at least up to clinical data cutoff date (31-JAN-2018).
    End point values
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population)
    Number of subjects analysed
    79 [4]
    42 [5]
    Units: Percent
        number (not applicable)
    69.1
    79.1
    Attachments
    Kaplan-Meier Plot for OS (ITT)
    Notes
    [4] - 49 patients from arm A were censored for analysis.
    [5] - 30 patients from arm B were censored for analysis.
    Statistical analysis title
    Kaplan-Meier Method
    Statistical analysis description
    Kaplan-Meier method was used for analysis of OS. Patients lost to follow-up and patients who withdrew from the study were censored at the time of last contact or time of withdrawal, respectively. Data of patients alive at their individual end of study were censored at date of last contact or, if this was not available, at date of last visit.
    Comparison groups
    Arm A - tecemotide + cyclophosphamide (ITT population) v Arm B - placebo + saline - (ITT population)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2141
    Method
    stratified Logrank-Test
    Confidence interval

    Secondary: 3-year RFS of MUC1 positive cancer patients

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    End point title
    3-year RFS of MUC1 positive cancer patients
    End point description
    The 3-year RFS rate of MUC1 positive cancer patients was defined as time from date of randomisation until date of recurrence of disease or date of death if no recurrence was documented and was analysed using Kaplan-Meier-Method.
    End point type
    Secondary
    End point timeframe
    The timeframe for 3-year RFS analysis was from date of randomisation until recurrence or death, whichever occured first. Observation of RFS was limited to 36 months from date of randomisation.
    End point values
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population)
    Number of subjects analysed
    79 [6]
    42 [7]
    Units: Percent
    number (not applicable)
        low MUC1 staining
    36.4
    0.0
        moderate MUC1 staining
    14.6
    20.8
        strong MUC1 staining
    22.7
    44.4
    Attachments
    Kaplan-Meier Plot for 3-year RFS stratified byMUC1
    Notes
    [6] - Censored patients Arm A for low (n=4), moderate (n=6) and strong (n=5) MUC1 staining.
    [7] - Censored patients Arm B for low (n=0), moderate (n=4) and strong (n=6) MUC1 staining.
    No statistical analyses for this end point

    Secondary: 3-year OS of MUC1 positive cancer patients

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    End point title
    3-year OS of MUC1 positive cancer patients
    End point description
    3-year OS was analysed using Kaplan-Meier-Method.
    End point type
    Secondary
    End point timeframe
    OS time was computed as time from date of randomisation up to clinical data cutoff date (31-JAN-2018).
    End point values
    Arm A - tecemotide + cyclophosphamide (ITT population) Arm B - placebo + saline - (ITT population)
    Number of subjects analysed
    79 [8]
    42 [9]
    Units: Percent
    number (not applicable)
        low MUC1 staining
    66.3
    60.0
        moderate MUC1 staining,
    78.7
    83.0
        strong MUC1 staining,
    74.7
    85.7
    Attachments
    Kaplan-Meier Plot for 3-year OS stratified by MUC1
    Notes
    [8] - Censored patients Arm A for low (n=8), moderate (n=22) and strong (n=14) MUC1 staining.
    [9] - Censored patients Arm B for low (n=3), moderate (n=14) and strong (n=7) MUC1 staining.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The (S)AE reporting period for safety surveillance began when the subject was enrolled in the trial and continued through the trial, until End of Treatment visit. Any SAE supected to be related to treatment must have been reported, whenever it occured.
    Adverse event reporting additional description
    At each trial visit, the subject was queried on condition changes. During the reporting period of the trial any unfavorable changes in the subject’s condition were recorded as (S)AEs. Any AE that occured during the course of the clinical trial and was suspected to be related to the IMP and all (S)AEs have been monitored and followed up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Arm A - tecemotide + cyclophosphamide - Safety Population
    Reporting group description
    Safety endpoints were assessed for all patients who were treated with at least iv cyclophosphamide and for whom follow-up safety data was documented (= Safety Population). For patients who withdrew from the trial or were lost to follow-up, AEs were recorded and analysed until the time of withdrawal or time of last contact. The numbers provided are treatment emergent events.

    Reporting group title
    Arm B - placebo + saline - Safety population
    Reporting group description
    Safety endpoints were assessed for all patients who were treated with at least iv saline and for whom follow-up safety data was documented (= Safety Population). For patients who withdrew from the trial or were lost to follow-up, AEs were recorded and analysed until the time of withdrawal or time of last contact. The numbers provided are treatment emergent events.

    Serious adverse events
    Arm A - tecemotide + cyclophosphamide - Safety Population Arm B - placebo + saline - Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 79 (29.11%)
    14 / 42 (33.33%)
         number of deaths (all causes)
    30
    12
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to abdominal wall
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Enterostomy
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Postpartum haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site induration
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopleural fistula
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pickwickian syndrome
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative delirium
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Kidney congestion
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A - tecemotide + cyclophosphamide - Safety Population Arm B - placebo + saline - Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 79 (87.34%)
    40 / 42 (95.24%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 42 (9.52%)
         occurrences all number
    7
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 42 (4.76%)
         occurrences all number
    10
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 79 (24.05%)
    8 / 42 (19.05%)
         occurrences all number
    27
    11
    Injection site erythema
         subjects affected / exposed
    7 / 79 (8.86%)
    1 / 42 (2.38%)
         occurrences all number
    17
    2
    Injection site reaction
         subjects affected / exposed
    6 / 79 (7.59%)
    3 / 42 (7.14%)
         occurrences all number
    25
    11
    Injection site swelling
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 42 (9.52%)
         occurrences all number
    4
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 42 (7.14%)
         occurrences all number
    6
    4
    Abdominal pain upper
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2
    Diarrhoea
         subjects affected / exposed
    15 / 79 (18.99%)
    7 / 42 (16.67%)
         occurrences all number
    21
    10
    Flatulence
         subjects affected / exposed
    2 / 79 (2.53%)
    6 / 42 (14.29%)
         occurrences all number
    2
    6
    Nausea
         subjects affected / exposed
    24 / 79 (30.38%)
    8 / 42 (19.05%)
         occurrences all number
    28
    8
    Vomiting
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 42 (14.29%)
         occurrences all number
    3
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 42 (7.14%)
         occurrences all number
    5
    3
    Erythema
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 42 (4.76%)
         occurrences all number
    8
    2
    Pruritus
         subjects affected / exposed
    3 / 79 (3.80%)
    6 / 42 (14.29%)
         occurrences all number
    3
    11
    Rash
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 42 (7.14%)
         occurrences all number
    4
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 79 (6.33%)
    5 / 42 (11.90%)
         occurrences all number
    6
    7
    Back pain
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 42 (4.76%)
         occurrences all number
    7
    5
    Pain in extremity
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 42 (2.38%)
         occurrences all number
    5
    1
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 42 (7.14%)
         occurrences all number
    1
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    14 / 79 (17.72%)
    4 / 42 (9.52%)
         occurrences all number
    14
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2011
    The following changes were implemented through the first amendment of the protocol (V.2.0 to V.3.0): The frequency of pregnancy testing was increased to monthly for Austrian female subjects as requested by the austrian ethics comittee.
    26 Sep 2012
    The following changes were implemented through the second amendment of the protocol (V.3.0 to V.4.0): The inclusion criteria were adapted and the time between resection and randomization was extended to give patients more time to recover from operation and participate in adequate rehabilitation measures.
    03 Mar 2015
    The following changes were implemented through the third amendment of the protocol (V.4.0 to V.5.0): • The treatment period was shortened from 3 to 2 years as the development of tecemotide for Non Small Cell Lung Cancer was discontinued by Merck KGaA. • Study endpoints were changed. As per original study protocol, the primary endpoint was RFS; 3-year OS rate was added as a co-primary endpoint. • Sample size calculation was changed. The sample size was reduced from 159 to 120 patients due to slow recruitment and issues regarding supply of medication. • The reporting period for AEs was changed. AEs suspected to be related to the investigational product had to be recorded until the end of the treatment evaluation (12 weeks after last treatment). SAEs suspected to be related to the investigational product had to be reported during whole follow up period. • The recruitment period was extended from Q3 2013 to Q4 2014. • Handling of medication after reconstitution was amended. Update according to handling instruction v2.0. • The inclusion criterion regarding coagulation was changed. Anticoagulated patients were allowed in the trial. • The end of follow-up period was changed to 3 years after randomization of last patient. • The number and total volume of blood sampling for translational program was changed. • The definition of the evaluation of RFS time was changed. Individual treatment time was limited until recurrence or a maximum of 2 years. • The current investigational status was changed. Clinical development of tecemotide has been discontinued.

    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.
    The trial served as a signal-finding study; statistically analyses have to be considered as fully explorative; high fraction of censored patients and a low number of patients in subgroup analysis limiting the explanatory power of Kaplan-Meier curves.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/22494623
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    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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