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    Clinical Trial Results:
    Open-label, Randomized, Controlled, Multicenter Phase II Trial Investigating 2 Sym004 Doses versus Investigator`s Choice (Best Supportive Care, Capecitabine, 5-FU) in Subjects with Metastatic Colorectal Cancer and Acquired Resistance to Anti-EGFR Monoclonal Antibodies

    Summary
    EudraCT number
    2013-003829-29
    Trial protocol
    DE   IT   BE   AT   HU   ES   PL  
    Global end of trial date
    26 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Apr 2019
    First version publication date
    26 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Sym004-05
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02083653
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Previous Protocol Code (Merck KGaA): EMR200637-002
    Sponsors
    Sponsor organisation name
    Symphogen A/S
    Sponsor organisation address
    Pederstrupvej 93, Ballerup, Denmark, 2750
    Public contact
    Chief Scientific Officer, Symphogen A/S, +45 88382600, info@symphogen.com
    Scientific contact
    Chief Scientific Officer, Symphogen A/S, +45 88382600, info@symphogen.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
    24 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of two different weekly dosing regimens of Sym004 compared with Investigator`s choice in terms of overall survival time in subjects with metastatic colorectal cancer (mCRC) and acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs).
    Protection of trial subjects
    Prophylactic and reactive treatment guidelines for skin management were implemented in this trial to reduce the incidence of severe rash. Based on data derived from randomized controlled trials using this approach (e.g., Skin Toxicity Evaluation Protocol with Panitumumab [STEPP] trial), it was anticipated that the incidence of Grade 3 rash would be reduced by these measures. Subjects receiving Sym004 were monitored weekly for hypomagnesemia, and intravenous replacement treatment was instituted twice weekly for Grade 3 and Grade 4 toxicity. Premedication to avoid or minimize infusion-related reactions (IRRs) to Sym004 was mandated during the treatment period. The subjects were monitored for at least 1 hour post-infusion.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Mar 2014
    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
    Poland: 25
    Country: Number of subjects enrolled
    Spain: 73
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Russian Federation: 30
    Worldwide total number of subjects
    254
    EEA total number of subjects
    202
    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)
    145
    From 65 to 84 years
    105
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Male or female, at least 18 years of age with histologically or cytologically confirmed mCRC, KRAS WT at initial diagnosis. Failure of or intolerance to 5-FU, Oxaliplatin, and Irinotecan. Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol. Measurable disease defined as one or more target lesions according to RECIST.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: Sym004 (12 mg/kg)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sym004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Sym004 was administered as an intravenous infusion at a dose of 12 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal. The first administration of Sym004 was performed on the same day as randomization or no later than 72 hours after randomization.

    Arm title
    Arm B: Sym004 (9/6 mg/kg)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sym004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Sym004 was administered as an intravenous infusion at a loading dose of 9 mg/kg followed by 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal. The first administration of Sym004 was performed on the same day as randomization or no later than 72 hours after randomization.

    Arm title
    Arm C: Investigator's Choice
    Arm description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.
    Arm type
    Active Comparator or BSC

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Started
    83
    86
    85
    Completed
    83
    86
    85
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: Sym004 (12 mg/kg)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sym004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Sym004 was administered as an intravenous infusion at a dose of 12 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal. The first administration of Sym004 was performed on the same day as randomization or no later than 72 hours after randomization.

    Arm title
    Arm B: Sym004 (9/6 mg/kg)
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sym004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Sym004 was administered as an intravenous infusion at a loading dose of 9 mg/kg followed by 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal. The first administration of Sym004 was performed on the same day as randomization or no later than 72 hours after randomization.

    Arm title
    Arm C: Investigator's Choice
    Arm description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.
    Arm type
    Active Comparator or BSC

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Started
    83
    84
    78
    Completed
    1
    1
    1
    Not completed
    82
    83
    77
         Progressive disease
    65
    73
    63
         Death
    2
    2
    2
         Reason missing
    -
    -
    4
         Adverse event, non-fatal
    12
    5
    4
         Consent withdrawn by subject
    2
    1
    2
         Other Events
    -
    2
    2
         Lost to follow-up
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: In Arm A, all randomized subjects (83) were treated. In Arm B, 86 subjects were randomized, but only 84 subjects were treated. In Arm C, 85 subjects were randomized, but only 78 subjects were treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Sym004 (12 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm B: Sym004 (9/6 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm C: Investigator's Choice
    Reporting group description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.

    Reporting group values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice Total
    Number of subjects
    83 86 85 254
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age is relative to time of informed consent for this trial. Age was omitted for privacy reasons for 5 subjects in Germany. In the Subjects Enrolled per Age Group, a mean age of 63 years was used for the 5 German subjects.
    Units: years
        arithmetic mean (standard deviation)
    62.2 ± 9.91 64.2 ± 10.41 61.4 ± 10.70 -
    Gender categorical
    Units: Subjects
        Female
    31 32 31 94
        Male
    52 54 54 160
    Ethnicity
    Ethnicity is presented as 'Not Reported’ for subjects living in France.
    Units: Subjects
        Hispanic or Latino
    5 5 5 15
        Not Hispanic or Latino
    69 72 70 211
        Unknown or not reported
    9 9 10 28
    Race
    Race is presented as 'Not Reported’ for subjects living in France.
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    1 0 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    1 2 0 3
        White
    72 75 73 220
        More than one race
    0 0 0 0
        Unknown or Not Reported
    9 9 12 30
    Region of Enrollment
    Units: Subjects
        Austria
    0 1 1 2
        Belgium
    3 6 5 14
        Hungary
    0 1 5 6
        United States
    8 6 8 22
        Poland
    10 8 7 25
        Italy
    17 12 20 49
        France
    9 9 10 28
        Germany
    4 0 1 5
        Russia
    8 12 10 30
        Spain
    24 31 18 73
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    168.9 ± 10.82 169.1 ± 9.71 167.9 ± 9.56 -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    75.3 ± 13.51 74.0 ± 14.14 76.0 ± 16.13 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.5 ± 4.43 25.8 ± 4.26 26.8 ± 4.59 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Sym004 (12 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm B: Sym004 (9/6 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm C: Investigator's Choice
    Reporting group description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.
    Reporting group title
    Arm A: Sym004 (12 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm B: Sym004 (9/6 mg/kg)
    Reporting group description
    -

    Reporting group title
    Arm C: Investigator's Choice
    Reporting group description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.

    Primary: Overall Survival (OS) Time

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    End point title
    Overall Survival (OS) Time
    End point description
    OS based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley. If a subject had not died, survival time was censored at the last date the subject was known to be alive. The analysis population was the intent-to-treat (ITT) subpopulation, which includes all subjects who were randomized to investigational medicinal product (IMP). Analyses performed on the ITT analysis set will take into account subjects’ allocation to treatment groups as randomized and not as treated.
    End point type
    Primary
    End point timeframe
    From randomization until the date of death (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83
    86
    85
    Units: Months
        median (confidence interval 95%)
    7.9 (6.5 to 9.9)
    10.3 (9.0 to 12.9)
    9.6 (8.3 to 12.2)
    Statistical analysis title
    Hazard ratio for Arm A vs. Arm C
    Statistical analysis description
    A Hazard ratio < 1 favors the Sym004 arm.
    Comparison groups
    Arm A: Sym004 (12 mg/kg) v Arm C: Investigator's Choice
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.137
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    1.87
    Statistical analysis title
    Hazard ratio for Arm B vs. Arm C
    Statistical analysis description
    A Hazard ratio < 1 favors the Sym004 arm.
    Comparison groups
    Arm B: Sym004 (9/6 mg/kg) v Arm C: Investigator's Choice
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.882
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.4

    Secondary: Best Overall Response (OR) According to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    Best Overall Response (OR) According to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    Tumor assessments were done via CT or magnetic resonance imaging (MRI) scans and evaluated per RECIST v1.1. The assessment for measurable disease during screening (within 14 days prior to Day 1) acts as the baseline assessment. Best OR was summarized for each treatment group by means of counts and percentages for the following categories: Complete Response (CR: disappearance of all target lesions), Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions), Progressive Disease (PD: at least a 20% increase in the sum of diameters of target lesions), Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) or Not Evaluable (NE). The analysis population was the ITT subpopulation, which includes all subjects who were randomized to IMP. Analyses performed on the ITT analysis set will take into account subjects allocation to treatment group as randomized and not as treated.
    End point type
    Secondary
    End point timeframe
    From randomization until first radiological confirmed or clinical progression event, or death due to any cause, within 12 weeks after last tumor assessment (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83
    86
    85
    Units: Participants
        Complete Response (CR)
    0
    0
    1
        Partial Response (PR)
    11
    8
    1
        Stable Disease (SD)
    40
    47
    37
        Progressive Disease (PD)
    27
    28
    31
        Not Evaluable (NE)
    5
    3
    15
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Time

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    End point title
    Progression Free Survival (PFS) Time
    End point description
    PFS based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley. Death will only be considered as an event if it occurs within 12 weeks after last tumor response assessment without progression. The analysis population was the ITT subpopulation, which includes all subjects who were randomized to IMP. Analyses performed on the ITT analysis set will take into account subjects’ allocation to treatment groups as randomized and not as treated.
    End point type
    Secondary
    End point timeframe
    From randomization until first event, where an event can be a progression (radiological confirmed or clinical progression) or death due to any cause (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83
    86
    85
    Units: Months
        median (confidence interval 95%)
    2.8 (1.8 to 3.2)
    2.7 (2.6 to 3.3)
    2.6 (1.4 to 3.1)
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    Time to Treatment Failure (TTF)
    End point description
    TTF based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley. The analysis population was the ITT subpopulation, which includes all subjects who were randomized to IMP. Analyses performed on the ITT analysis set will take into account subjects’ allocation to treatment groups as randomized and not as treated. Subjects who were randomized but not treated have been censored at the date of randomization.
    End point type
    Secondary
    End point timeframe
    From randomization until treatment discontinuation for any reason, including disease progression or death (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83
    86
    85
    Units: Months
        median (confidence interval 95%)
    2.1 (1.4 to 2.7)
    2.6 (2.2 to 2.6)
    1.6 (1.2 to 2.7)
    No statistical analyses for this end point

    Secondary: Occurrence and Nature of Adverse Events (AEs), as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03).

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    End point title
    Occurrence and Nature of Adverse Events (AEs), as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03).
    End point description
    AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. The incidence and type of AEs (i.e., serious AE [SAE], treatment-emergent AE [TEAE]) were summarized by dose cohort according to MedDRA system organ classes and preferred terms. An AE was considered as treatment-emergent if it occurred during or after the first IMP administration. An AE that occurred before the first IMP administration and worsened thereafter was also considered an AE. Worsening was reported as a new AE. The analysis population was the safety analysis subpopulation, which includes all subjects who were administered any dose of IMP, and in addition those subjects in Arm C for which the intended control treatment is BSC. Subjects will be analyzed as treated and not as randomized.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 28 days after the last IMP administration.
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83
    84
    78
    Units: Participants
        At least one TEAE
    83
    84
    67
        At least one Serious TEAE
    27
    23
    12
        TEAE leading to dose reduction
    29
    17
    8
        TEAE leading to interruption of trial treatment
    58
    47
    10
        TEAE leading to trial treatment withdrawal
    12
    5
    6
        TEAE related to trial treatment
    81
    80
    46
        TEAE, Grade >=3
    67
    53
    25
        Dermatologic toxicity
    78
    78
    8
        Infusion-related reaction
    27
    26
    0
        TEAE resulting in death
    4
    4
    3
        Related Serious TEAE
    9
    6
    2
        Related TEAE leading to dose reduction
    29
    17
    6
        Related TEAE leading to interruption of treatment
    53
    42
    7
        Related TEAE leading to treatment withdrawal
    9
    2
    3
        Related TEAE, Grade >=3
    58
    41
    9
        Related TEAE resulting in death
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Relative Dose Intensity of Sym004

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    End point title
    Relative Dose Intensity of Sym004
    End point description
    Treatment duration (weeks) is calculated as [(last dose date of Sym004 - first dose date of Sym004)+7] / 7 days. Sym004 dose received (mg/kg) is calculated as (total dose administered (mg)/weight (kg)). Dose Intensity is calculated as (cumulative Sym004 dose (mg/kg) / treatment duration (weeks)). Relative Dose Intensity is calculated as (dose intensity / planned dose intensity at randomization)*100. Percentages are based on the number of subjects in the safety analysis set. The analysis population was the safety analysis subpopulation, which includes all subjects who were administered any dose of IMP. Subjects will be analyzed as treated and not as randomized.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until disease progression (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg)
    Number of subjects analysed
    83
    84
    Units: Percentage of relative dose intensity
        arithmetic mean (standard deviation)
    80.49 ± 20.020
    88.91 ± 13.843
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Sym004 Concentrations

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    End point title
    Pharmacokinetic (PK) Parameters: Sym004 Concentrations
    End point description
    The Sym004 serum concentration used for the PK evaluation was calculated as the sum of the serum concentrations of the 2 component monoclonal antibodies of Sym004, futuximab and modotuximab. Trough Concentration (Ctrough) is equivalent to the concentration collected at the pre-dose timepoint. Maximum Concentration (Cmax) is equivalent to the concentration collected at the end of infusion (EOI) timepoint. The analysis population was the PK analysis set. Bioanalysis for serum concentration was done for a subset of subjects (N=19) at all scheduled timepoints; it was carried out only at Weeks 3, 5, 7 and the End of Treatment visit (EOT) for all other subjects. Additionally, the Week 1 Day 1 EOI concentration for Subject 2740012 was assessed.
    End point type
    Secondary
    End point timeframe
    Weeks 3, 5, and 7 and at the EOT visit, including a Week 1 and Week 2 subset.
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg)
    Number of subjects analysed
    80 [1]
    83 [2]
    Units: ug/ml
    arithmetic mean (standard deviation)
        Screening (Pre-dose)
    0.50 ± 0.0
    0.50 ± 0.0
        Week 1 Day 1 (Pre-dose)
    0.50 ± 0.0
    0.75 ± 0.700
        Week 1 Day 1 (EOI)
    182.95 ± 97.686
    174.44 ± 47.023
        Week 1 Day 1 (0.5 hours after EOI)
    214.98 ± 46.242
    184.84 ± 33.103
        Week 1 Day 1 (1 hours after EOI)
    209.80 ± 60.707
    189.24 ± 38.923
        Week 1 Day 1 (2 hours after EOI)
    197.31 ± 65.801
    181.68 ± 37.577
        Week 1 Day 1 (4 hours after EOI)
    188.75 ± 68.421
    171.63 ± 35.862
        Week 2 Day 1 (Pre-dose)
    45.37 ± 28.604
    38.76 ± 10.311
        Week 2 Day 1 (EOI)
    275.42 ± 80.975
    145.91 ± 47.950
        Week 3 Day 1 (Pre-dose)
    92.66 ± 38.443
    44.26 ± 20.995
        Week 3 Day 1 (EOI)
    323.35 ± 83.412
    170.18 ± 50.323
        Week 5 Day 1 (Pre-dose)
    125.73 ± 61.644
    49.26 ± 30.252
        Week 5 Day 1 (EOI)
    354.91 ± 108.263
    168.94 ± 67.901
        Week 7 Day 1 (Pre-dose)
    128.30 ± 77.437
    58.38 ± 47.505
        Week 7 Day 1 (EOI)
    346.83 ± 136.083
    163.11 ± 74.967
        End of Treatment
    64.55 ± 79.250
    17.61 ± 24.474
    Notes
    [1] - Overall number of subjects analyzed was 80. The number of subjects analyzed varied per timepoint.
    [2] - Overall number of subjects analyzed was 83. The number of subjects analyzed varied per timepoint.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Time of Maximum Plasma Concentration (Tmax)

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    End point title
    Pharmacokinetic (PK) Parameters: Time of Maximum Plasma Concentration (Tmax)
    End point description
    Tmax was defined as the time the PK sample was taken at end of infusion (EOI) relative to the start time of infusion (i.e., time between the start of infusion and the time of the EOI sample). For presentation of individual PK parameters and calculation of mean parameters, half of the lower limit of quantitation (LLOQ) value was used for concentration values below the LLOQ. The Sym004 serum concentration used for the PK evaluation was calculated as the sum of the serum concentrations of the 2 component monoclonal antibodies of Sym004 (futuximab and modotuximab). The analysis population was the PK analysis set, defined as subjects having at least 1 Sym004 serum concentration above the LLOQ. Exposure to Sym004 was confirmed in the majority of subjects treated with Sym004 for at least 1 timepoint post-dose.
    End point type
    Secondary
    End point timeframe
    Day 1 on Weeks 1-3 followed by Week 5 Day 1 and Week 7 Day 1.
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg)
    Number of subjects analysed
    80 [3]
    83 [4]
    Units: Hours
    arithmetic mean (standard deviation)
        Week 1 Day 1
    3.14 ± 0.822
    2.79 ± 0.210
        Week 2 Day 1
    2.82 ± 0.306
    2.33 ± 0.459
        Week 3 Day 1
    3.01 ± 0.555
    2.34 ± 0.477
        Week 5 Day 1
    2.74 ± 0.532
    2.06 ± 0.448
        Week 7 Day 1
    2.83 ± 0.867
    2.06 ± 0.473
    Notes
    [3] - Overall number of subjects analyzed was 80. The number of subjects analyzed varied per visit.
    [4] - Overall number of subjects analyzed was 83. The number of subjects analyzed varied per visit.
    No statistical analyses for this end point

    Secondary: Host Immune Response: Number of Subjects With Anti-drug Antibodies (ADAs) to Sym004 Over Time

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    End point title
    Host Immune Response: Number of Subjects With Anti-drug Antibodies (ADAs) to Sym004 Over Time
    End point description
    A validated double antigen bridging ELISA was used for screening, confirmation, and titration of patient samples for anti-Sym004 ADA. Using rabbit anti-Sym004 as an ADA control antibody, the lower limit of detection was 54 ng/mL in the absence of Sym004 and 500 ng/mL in the presence of Sym004 at 5 μg/mL The timepoints for ADA sampling were chosen by the original sponsor for this trial. After the trial was transferred to Symphogen A/S, it was determined that not all samples were necessary for analysis. This is why the collection time points specified in the timeframe do not match with the data table. The analysis population was the safety analysis subpopulation, which includes all subjects who were administered any dose of IMP. Subjects will be analyzed as treated and not as randomized.
    End point type
    Secondary
    End point timeframe
    Every two weeks (Days 15, 29, and 43) followed by every six weeks thereafter (Days 78, 120, 162, etc.) until the End of Treatment Visit
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg)
    Number of subjects analysed
    83
    84
    Units: Participants
        Screening, Negative
    78
    81
        Screening, Positive
    2
    0
        Screening, Not Reportable
    1
    0
        Screening, Missing
    2
    3
        Week 5 Day 1, Negative
    59
    62
        Week 5 Day 1, Positive
    0
    0
        Week 5 Day 1, Not Reportable
    0
    0
        Week 5 Day 1, Missing
    24
    22
        Week 12, Negative
    24
    35
        Week 12, Positive
    0
    0
        Week 12, Not Reportable
    0
    0
        Week 12, Missing
    59
    49
        Week 13, Negative
    1
    1
        Week 13, Positive
    0
    0
        Week 13, Not Reportable
    0
    0
        Week 13, Missing
    82
    83
        Week 24, Negative
    0
    1
        Week 24, Positive
    0
    0
        Week 24, Not Reportable
    0
    0
        Week 24, Missing
    83
    83
        End of Treatment Visit, Negative
    60
    55
        End of Treatment Visit, Positive
    0
    0
        End of Treatment Visit, Not Reportable
    0
    0
        End of Treatment Visit, Missing
    23
    29
    No statistical analyses for this end point

    Secondary: Quality of Life Assessed by the EORTC QLQ-C30 (Version 3)

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    End point title
    Quality of Life Assessed by the EORTC QLQ-C30 (Version 3)
    End point description
    Scale: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (Version 3) [QLQ-C30, Version 3]. The QLQ-C30 is a 30-question scale used to assess cancer patients' quality of life based on 15 factors (e.g., global health status, physical functioning, role functioning, etc.). The scale is composed of both multi-item scales and single item measures. All of the scales and single-item measures range in score from 0 to 100: • A high score for a functional scale represents a healthy level of functioning. • A high score for the global health status represents a high quality of life. • A high score for a symptom scale/item represents a high level of symptomatology (problems). This measure was self-reported. Numbers analyzed between Week 1 and Week 7 differ from each other, as well from the overall number of subjects analyzed. Data could not be collected from subjects not compliant with reporting or once discontinued.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks (week 1 and week 7 reported)
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83 [5]
    86 [6]
    85 [7]
    Units: score on a scale
    arithmetic mean (full range (min-max))
        Global Health Status (Week 1 Day 1)
    55.5 (0 to 92)
    59.7 (8 to 100)
    55.8 (8 to 100)
        Global Health Status (Week 7 Day 1)
    57.4 (25 to 100)
    59.4 (17 to 100)
    59.7 (17 to 100)
        Physical Functioning (Week 1 Day 1)
    76.4 (7 to 100)
    78.7 (27 to 100)
    77.7 (27 to 100)
        Physical Functioning (Week 7 Day 1)
    82.1 (13 to 100)
    83.0 (47 to 100)
    76.7 (40 to 100)
        Role Functioning (Week 1 Day 1)
    75.0 (0 to 100)
    76.4 (0 to 100)
    72.5 (0 to 100)
        Role Functioning (Week 7 Day 1)
    81.1 (33 to 100)
    82.4 (50 to 100)
    72.8 (17 to 100)
        Emotional Functioning (Week 1 Day 1)
    76.6 (17 to 100)
    77.8 (17 to 100)
    73.2 (0 to 100)
        Emotional Functioning (Week 7 Day 1)
    74.8 (0 to 100)
    82.7 (33 to 100)
    75.3 (17 to 100)
        Cognitive Functioning (Week 1 Day 1)
    87.4 (33 to 100)
    86.2 (17 to 100)
    87.5 (50 to 100)
        Cognitive Functioning (Week 7 Day 1)
    88.1 (33 to 100)
    88.5 (33 to 100)
    87.0 (33 to 100)
        Social Functioning (Week 1 Day 1)
    78.2 (17 to 100)
    80.2 (17 to 100)
    75.4 (17 to 100)
        Social Functioning (Week 7 Day 1)
    77.9 (0 to 100)
    83.4 (50 to 100)
    72.7 (0 to 100)
        Fatigue Symptoms (Week 1 Day 1)
    35.3 (0 to 89)
    32.2 (0 to 100)
    34.7 (0 to 100)
        Fatigue Symptoms (Week 7 Day 1)
    26.3 (0 to 78)
    25.3 (0 to 78)
    33.2 (0 to 78)
        Nausea & Vomiting Symptoms (Week 1 Day 1)
    7.9 (0 to 67)
    6.4 (0 to 100)
    7.8 (0 to 83)
        Nausea & Vomiting Symptoms (Week 7 Day 1)
    5.6 (0 to 33)
    5.1 (0 to 50)
    8.4 (0 to 50)
        Pain Symptoms (Week 1 Day 1)
    27.2 (0 to 100)
    23.6 (0 to 100)
    27.8 (0 to 100)
        Pain Symptoms (Week 7 Day 1)
    12.7 (0 to 50)
    14.6 (0 to 67)
    24.1 (0 to 83)
        Dyspnoea Symptoms (Week 1 Day 1)
    15.9 (0 to 100)
    17.2 (0 to 100)
    16.4 (0 to 100)
        Dyspnoea Symptoms (Week 7 Day 1)
    10.4 (0 to 67)
    8.8 (0 to 100)
    15.7 (0 to 100)
        Insomnia Symptoms (Week 1 Day 1)
    29.3 (0 to 100)
    19.1 (0 to 100)
    21.7 (0 to 100)
        Insomnia Symptoms (Week 7 Day 1)
    27.4 (0 to 100)
    16.9 (0 to 100)
    16.6 (0 to 67)
        Appetite Loss Symptoms (Week 1 Day 1)
    22.3 (0 to 100)
    17.6 (0 to 100)
    22.2 (0 to 100)
        Appetite Loss Symptoms (Week 7 Day 1)
    16.9 (0 to 100)
    17.5 (0 to 67)
    23.0 (0 to 100)
        Constipation Symptoms (Week 1 Day 1)
    15.0 (0 to 67)
    16.0 (0 to 100)
    11.4 (0 to 100)
        Constipation Symptoms (Week 7 Day 1)
    11.5 (0 to 67)
    8.3 (0 to 67)
    11.1 (0 to 67)
        Diarrhoea Symptoms (Week 1 Day 1)
    12.5 (0 to 100)
    8.5 (0 to 100)
    15.9 (0 to 100)
        Diarrhoea Symptoms (Week 7 Day 1)
    8.8 (0 to 100)
    11.1 (0 to 67)
    11.0 (0 to 67)
        Financial Difficulties (Week 1 Day 1)
    19.7 (0 to 67)
    16.6 (0 to 100)
    23.3 (0 to 100)
        Financial Difficulties (Week 7 Day 1)
    19.4 (0 to 100)
    15.2 (0 to 67)
    19.3 (0 to 100)
    Notes
    [5] - Overall number of subjects analyzed was 83. Number of subjects analyzed varied per visit.
    [6] - Overall number of subjects analyzed was 86. Number of subjects analyzed varied per visit.
    [7] - Overall number of subjects analyzed was 85. Number of subjects analyzed varied per visit.
    No statistical analyses for this end point

    Secondary: Quality of Life Assessed by the EORTC QLQ-CR29

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    End point title
    Quality of Life Assessed by the EORTC QLQ-CR29
    End point description
    Scale: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Colorectal Cancer Module (QLQ-CR29). The QLQ-CR29 is a 29-question scale used to assess colorectal cancer patients' quality of life based on 22 factors (e.g., body image, anxiety, weight, etc.). The scale is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100: • A high score for a functional scale/item represents an unhealthy level of functioning, with the exception of one (1) scale pertaining to sexual interest (separated by sex). • A high score for a symptom scale/item represents a high level of symptomatology (problems). This measure was self-reported. Numbers analyzed between Week 1 and Week 7 differ from each other, as well from the overall number of subjects analyzed. Data could not be collected from subjects not compliant with reporting or once discontinued.
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks (week 1 and week 7 reported)
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83 [8]
    86 [9]
    85 [10]
    Units: score on a scale
    arithmetic mean (full range (min-max))
        Body Image (Week 1 Day 1)
    76.2 (0 to 100)
    80.1 (1 to 100)
    75.8 (0 to 100)
        Body Image (Week 7 Day 1)
    76.4 (11 to 100)
    77.6 (33 to 100)
    78.2 (0 to 100)
        Anxiety (Week 1 Day 1)
    50.0 (0 to 100)
    48.2 (0 to 100)
    43.0 (0 to 100)
        Anxiety (Week 7 Day 1)
    57.1 (0 to 100)
    61.1 (0 to 100)
    50.9 (0 to 100)
        Weight (Week 1 Day 1)
    79.5 (0 to 100)
    85.6 (0 to 100)
    78.3 (0 to 100)
        Weight (Week 7 Day 1)
    86.6 (33 to 100)
    89.6 (33 to 100)
    88.0 (0 to 100)
        Sexual Function (Men) (Week 1 Day 1)
    31.7 (0 to 100)
    21.2 (0 to 100)
    23.5 (0 to 100)
        Sexual Function (Men) (Week 7 Day 1)
    33.2 (0 to 100)
    26.6 (0 to 67)
    34.9 (0 to 100)
        Sexual Function (Women) (Week 1 Day 1)
    16.5 (0 to 33)
    12.3 (0 to 67)
    10.1 (0 to 67)
        Sexual Function (Women) (Week 7 Day 1)
    16.6 (0 to 67)
    13.6 (0 to 67)
    11.0 (0 to 33)
        Urinary Frequency (Week 1 Day 1)
    34.4 (0 to 100)
    30.3 (0 to 83)
    32.6 (0 to 100)
        Urinary Frequency (Week 7 Day 1)
    28.2 (0 to 100)
    28.8 (0 to 67)
    18.5 (0 to 67)
        Blood and Mucus (Week 1 Day 1)
    4.1 (0 to 50)
    1.5 (0 to 33)
    2.0 (0 to 33)
        Blood and Mucus (Week 7 Day 1)
    2.6 (0 to 33)
    3.1 (0 to 67)
    2.3 (0 to 33)
        Stool Frequency (Week 1 Day 1)
    15.5 (0 to 100)
    11.3 (0 to 100)
    14.1 (0 to 83)
        Stool Frequency (Week 7 Day 1)
    13.4 (0 to 50)
    11.8 (0 to 83)
    13.1 (0 to 67)
        Urinary Incontinence (Week 1 Day 1)
    8.2 (0 to 100)
    7.5 (0 to 100)
    7.4 (0 to 100)
        Urinary Incontinence (Week 7 Day 1)
    7.0 (0 to 67)
    4.8 (0 to 67)
    1.9 (0 to 33)
        Dysuria (Week 1 Day 1)
    4.0 (0 to 33)
    2.9 (0 to 67)
    3.0 (0 to 67)
        Dysuria (Week 7 Day 1)
    3.2 (0 to 33)
    2.1 (0 to 33)
    0.9 (0 to 33)
        Abdominal Pain (Week 1 Day 1)
    18.8 (0 to 100)
    12.8 (0 to 100)
    23.0 (0 to 100)
        Abdominal Pain (Week 7 Day 1)
    10.4 (0 to 67)
    10.8 (0 to 67)
    16.6 (0 to 67)
        Buttock Pain (Week 1 Day 1)
    11.6 (0 to 100)
    10.8 (0 to 100)
    9.9 (0 to 100)
        Buttock Pain (Week 7 Day 1)
    4.4 (0 to 33)
    8.8 (0 to 67)
    7.4 (0 to 67)
        Bloated Feeling (Week 1 Day 1)
    20.4 (0 to 100)
    14.8 (0 to 67)
    21.7 (0 to 100)
        Bloated Feeling (Week 7 Day 1)
    13.3 (0 to 67)
    12.1 (0 to 33)
    12.9 (0 to 67)
        Dry Mouth (Week 1 Day 1)
    25.1 (0 to 100)
    17.0 (0 to 67)
    22.1 (0 to 100)
        Dry Mouth (Week 7 Day 1)
    26.8 (0 to 100)
    29.2 (0 to 100)
    13.8 (0 to 67)
        Hair Loss (Week 1 Day 1)
    17.1 (0 to 100)
    11.1 (0 to 100)
    14.6 (0 to 100)
        Hair Loss (Week 7 Day 1)
    7.0 (0 to 100)
    7.6 (0 to 67)
    4.6 (0 to 100)
        Trouble with Taste (Week 1 Day 1)
    20.0 (0 to 100)
    13.9 (0 to 100)
    15.1 (0 to 100)
        Trouble with Taste (Week 7 Day 1)
    18.5 (0 to 100)
    15.2 (0 to 67)
    12.9 (0 to 100)
        Flatulence (Week 1 Day 1)
    18.3 (0 to 100)
    19.5 (0 to 100)
    23.1 (0 to 100)
        Flatulence (Week 7 Day 1)
    12.4 (0 to 67)
    16.1 (0 to 67)
    12.4 (0 to 33)
        Faecal Incontinence (Week 1 Day 1)
    8.9 (0 to 100)
    8.8 (0 to 100)
    7.1 (0 to 67)
        Faecal Incontinence (Week 7 Day 1)
    2.5 (0 to 33)
    7.3 (0 to 67)
    3.1 (0 to 33)
        Sore Skin (Week 1 Day 1)
    9.6 (0 to 67)
    8.8 (0 to 67)
    6.0 (0 to 33)
        Sore Skin (Week 7 Day 1)
    11.6 (0 to 33)
    9.7 (0 to 67)
    4.2 (0 to 67)
        Embarrassed by Bowel Movement (Week 1 Day 1)
    8.5 (0 to 100)
    7.8 (0 to 100)
    13.9 (0 to 100)
        Embarrassed by Bowel Movement (Week 7 Day 1)
    7.5 (0 to 67)
    8.1 (0 to 67)
    10.4 (0 to 67)
        Stoma Care Problem (Week 1 Day 1)
    16.6 (0 to 100)
    3.3 (0 to 33)
    6.6 (0 to 67)
        Stoma Care Problem (Week 7 Day 1)
    9.9 (0 to 33)
    2.4 (0 to 33)
    8.3 (0 to 33)
        Impotence (Week 1 Day 1)
    46.9 (0 to 100)
    38.7 (0 to 100)
    49.5 (0 to 100)
        Impotence (Week 7 Day 1)
    40.4 (0 to 100)
    42.7 (0 to 100)
    50.7 (0 to 100)
        Dyspareunia (Week 1 Day 1)
    12.1 (0 to 100)
    7.2 (0 to 33)
    11.0 (0 to 100)
        Dyspareunia (Week 7 Day 1)
    14.3 (0 to 67)
    10.3 (0 to 33)
    13.3 (0 to 67)
    Notes
    [8] - Overall number of subjects analyzed was 83. Number of subjects analyzed varied per visit.
    [9] - Overall number of subjects analyzed was 86. Number of subjects analyzed varied per visit.
    [10] - Overall number of subjects analyzed was 85. Number of subjects analyzed varied per visit.
    No statistical analyses for this end point

    Secondary: Quality of Life Assessed by FACT-EGFRI-18 for Skin Rash

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    End point title
    Quality of Life Assessed by FACT-EGFRI-18 for Skin Rash
    End point description
    Scale: Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor 18 (FACT-EGFRI-18). The FACT-EGFRI-18 is an 18-question scale used to assess EGFR-inhibitor-treated cancer patients' quality of life relative to their experience of skin rash based on three (3) multi-item subscales. The subscales combined (i.e., Symptom Index) range in score from 0 to 72. A higher score represents a high level of symptomatology (problems). High scores for all subscales represent a worse outcome: • The Physical subscale ranges in score from 0 to 28. • The Social/Emotional subscale ranges in score from 0 to 24. • The Functional subscale ranges in score from 0 to 20. This measure was self-reported. Numbers analyzed between Week 1 and Week 4 differ from each other, as well from the overall number of subjects analyzed. Data could not be collected from subjects not compliant with reporting or once discontinued.
    End point type
    Secondary
    End point timeframe
    Assessed every 3 weeks (week 1 and week 4 reported)
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    83 [11]
    86 [12]
    85 [13]
    Units: score on a scale
    arithmetic mean (full range (min-max))
        Physical (Week 1 Day 1)
    22.9 (2 to 28)
    23.1 (4 to 28)
    24.3 (6 to 28)
        Physical (Week 4 Day 1)
    18.0 (4 to 28)
    19.7 (5 to 28)
    25.1 (16 to 28)
        Social/Emotional (Week 1 Day 1)
    21.5 (9 to 24)
    21.5 (6 to 24)
    22.6 (9 to 24)
        Social/Emotional (Week 4 Day 1)
    19.9 (7 to 24)
    20.3 (5 to 24)
    23.2 (15 to 24)
        Functional (Week 1 Day 1)
    17.9 (5 to 20)
    18.3 (7 to 20)
    18.7 (4 to 20)
        Functional (Week 4 Day 1)
    16.3 (3 to 20)
    17.0 (6 to 20)
    19.3 (13 to 20)
        Symptom Index (Week 1 Day 1)
    62.3 (18 to 72)
    62.9 (20 to 72)
    65.6 (19 to 72)
        Symptom Index (Week 4 Day 1)
    54.2 (16 to 72)
    57.0 (22 to 72)
    67.6 (46 to 72)
    Notes
    [11] - Overall number of subjects analyzed was 83. Number of subjects analyzed varied per visit.
    [12] - Overall number of subjects analyzed was 86. Number of subjects analyzed varied per visit.
    [13] - Overall number of subjects analyzed was 85. Number of subjects analyzed varied per visit.
    No statistical analyses for this end point

    Post-hoc: Overall Survival (OS) Time for Patients in Europe + United States With Double-Negative mCRC (EU+US DNmCRC)

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    End point title
    Overall Survival (OS) Time for Patients in Europe + United States With Double-Negative mCRC (EU+US DNmCRC)
    End point description
    This endpoint is exploratory. Because of the unanticipated long OS in the control group, initial exploratory subgroup analyses identified that findings in patients enrolled in Russia differed when compared with patients enrolled in the ITT subpopulation and the EU+US subpopulation. For this reason, subjects in Russia were excluded from further exploratory subset analyses that evaluated the effects of genomic parameters known to impact patient responses to anti-EGFR mAbs. Removal of the outlier Russian patients provided a patient population that was more homogeneous with respect to their prior treatment regimens, thereby facilitating further exploratory analyses. If a subject had not died, survival time was censored at the last date the subject was known to be alive. The analysis population was the EU+US DNmCRC analysis set, which is a genomically-defined subpopulation excluding patients with high frequency clonal RAS mutations and BRAF V600E mutations.
    End point type
    Post-hoc
    End point timeframe
    From randomization until the date of death (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    62 [14]
    57 [15]
    51 [16]
    Units: months
        median (confidence interval 95%)
    8.9 (6.2 to 12.4)
    11.9 (9.7 to 13.8)
    8.4 (6.4 to 10.0)
    Notes
    [14] - Overall number of subjects analyzed for this endpoint.
    [15] - Overall number of subjects analyzed for this endpoint.
    [16] - Overall number of subjects analyzed for this endpoint.
    No statistical analyses for this end point

    Post-hoc: Overall Survival (OS) Time for Patients in Europe + United States With Triple-Negative mCRC (EU+US TNmCRC)

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    End point title
    Overall Survival (OS) Time for Patients in Europe + United States With Triple-Negative mCRC (EU+US TNmCRC)
    End point description
    This outcome measure is exploratory. Because of the unanticipated long OS in the control group, initial exploratory subgroup analyses identified that findings in patients enrolled in Russia differed when compared with patients enrolled in the ITT subpopulation and the EU+US subpopulation. For this reason, subjects in Russia were excluded from further exploratory subset analyses that evaluated the effects of genomic parameters known to impact patient responses to anti-EGFR mAbs. Removal of the outlier Russian patients provided a patient population that was more homogeneous with respect to their prior treatment regimens, thereby facilitating further exploratory analyses. If a subject had not died, survival time was censored at the last date the subject was known to be alive. The analysis population was the EU+US TNmCRC analysis set, which is a genomically-defined subpopulation excluding DNmCRC patients with six (6) selected EGFR extracellular domain (ECD) mutations.
    End point type
    Post-hoc
    End point timeframe
    From randomization until the date of death (assessed up to 32 months).
    End point values
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Number of subjects analysed
    47 [17]
    46 [18]
    38 [19]
    Units: months
        median (confidence interval 95%)
    10.6 (6.8 to 13.1)
    12.8 (9.7 to 14.7)
    7.3 (6.3 to 8.8)
    Notes
    [17] - Overall number of subjects analyzed for this endpoint.
    [18] - Overall number of subjects analyzed for this endpoint.
    [19] - Overall number of subjects analyzed for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data were collected beginning with the signing of informed consent and continued through the End of Trial Intervention Visit (i.e., no earlier than 28 days after stop of treatment). The AE data collection period was 38 months.
    Adverse event reporting additional description
    Subjects analyzed for serious AEs and non-serious AEs are based on the Safety Analysis Set. The Safety Analysis Set contained all subjects in the ITT Analysis Set who received at least one (1) dose of trial treatment (Sym004, 5-FU, or capecitabine) and in addition, those subjects who received Best Supportive Care only.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A: Sym004 (12 mg/kg)
    Reporting group description
    Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR. Sym004 was administered as an intravenous infusion at a dose of 12 milligrams per kilogram (mg/kg) weekly until unacceptable toxicity, disease progression, or consent withdrawal.

    Reporting group title
    Arm B: Sym004 (9/6 mg/kg)
    Reporting group description
    Sym004 is a 1:1 mixture of two mAbs (futuximab and modotuximab) which bind to two non-overlapping epitopes of the EGFR. Sym004 was administered as an intravenous infusion at a loading dose of 9 mg/kg followed by 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal.

    Reporting group title
    Arm C: Investigator's Choice
    Reporting group description
    Best supportive care (BSC) or Fluorouracil (5-FU, Adrucil) or Capecitabine (Xeloda) will be given as per Investigator's discretion. BSC was the best palliative care as per Investigator's discretion, excluding antineoplastic agents. BSC may include, but is not limited to, antibiotics, analgesics, antiemetics, blood transfusions, and nutritional support. 5-FU was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert. Capecitabine was to be administered at doses and schedules as per Investigator's discretion and in line with the local package insert.

    Serious adverse events
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 83 (32.53%)
    23 / 84 (27.38%)
    12 / 78 (15.38%)
         number of deaths (all causes)
    68
    62
    57
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Tumour haemorrhage
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    General physical health deterioration
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 84 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Oedema peripheral
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Spinal compression fracture
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Urinary tract stoma complication
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus node dysfunction
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Dyspnoea
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Pleural effusion
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Pneumonia aspiration
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 84 (1.19%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Pancreatitis acute
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Rectal obstruction
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Vomiting
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 84 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         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 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Vesicocutaneous fistula
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Erythema
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Skin toxicity
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Electrolyte imbalance
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Hypomagnesaemia
         subjects affected / exposed
    4 / 83 (4.82%)
    5 / 84 (5.95%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 84 (1.19%)
    0 / 78 (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
    Impetigo
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Pneumonia
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 84 (0.00%)
    0 / 78 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A: Sym004 (12 mg/kg) Arm B: Sym004 (9/6 mg/kg) Arm C: Investigator's Choice
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 83 (100.00%)
    84 / 84 (100.00%)
    67 / 78 (85.90%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 83 (7.23%)
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences all number
    7
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 83 (31.33%)
    21 / 84 (25.00%)
    14 / 78 (17.95%)
         occurrences all number
    34
    28
    16
    Chills
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 84 (5.95%)
    1 / 78 (1.28%)
         occurrences all number
    3
    7
    1
    Fatigue
         subjects affected / exposed
    8 / 83 (9.64%)
    7 / 84 (8.33%)
    14 / 78 (17.95%)
         occurrences all number
    9
    7
    16
    Mucosal inflammation
         subjects affected / exposed
    8 / 83 (9.64%)
    6 / 84 (7.14%)
    4 / 78 (5.13%)
         occurrences all number
    10
    6
    4
    Oedema peripheral
         subjects affected / exposed
    9 / 83 (10.84%)
    7 / 84 (8.33%)
    1 / 78 (1.28%)
         occurrences all number
    9
    7
    1
    Pyrexia
         subjects affected / exposed
    12 / 83 (14.46%)
    10 / 84 (11.90%)
    9 / 78 (11.54%)
         occurrences all number
    20
    11
    9
    Xerosis
         subjects affected / exposed
    26 / 83 (31.33%)
    12 / 84 (14.29%)
    0 / 78 (0.00%)
         occurrences all number
    28
    20
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 83 (10.84%)
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences all number
    9
    2
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    18 / 83 (21.69%)
    15 / 84 (17.86%)
    0 / 78 (0.00%)
         occurrences all number
    20
    18
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 83 (8.43%)
    8 / 84 (9.52%)
    0 / 78 (0.00%)
         occurrences all number
    10
    11
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 83 (9.64%)
    6 / 84 (7.14%)
    1 / 78 (1.28%)
         occurrences all number
    9
    8
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 83 (8.43%)
    10 / 84 (11.90%)
    6 / 78 (7.69%)
         occurrences all number
    8
    12
    9
    Blood bilirubin increased
         subjects affected / exposed
    5 / 83 (6.02%)
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences all number
    5
    3
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    6 / 83 (7.23%)
    7 / 84 (8.33%)
    2 / 78 (2.56%)
         occurrences all number
    12
    11
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    7 / 83 (8.43%)
    11 / 84 (13.10%)
    7 / 78 (8.97%)
         occurrences all number
    12
    17
    10
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 83 (1.20%)
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    1
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 83 (12.05%)
    15 / 84 (17.86%)
    11 / 78 (14.10%)
         occurrences all number
    12
    21
    17
    Leukopenia
         subjects affected / exposed
    4 / 83 (4.82%)
    7 / 84 (8.33%)
    5 / 78 (6.41%)
         occurrences all number
    4
    8
    12
    Neutropenia
         subjects affected / exposed
    2 / 83 (2.41%)
    4 / 84 (4.76%)
    9 / 78 (11.54%)
         occurrences all number
    2
    9
    13
    Thrombocytopenia
         subjects affected / exposed
    3 / 83 (3.61%)
    7 / 84 (8.33%)
    8 / 78 (10.26%)
         occurrences all number
    3
    13
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 84 (5.95%)
    5 / 78 (6.41%)
         occurrences all number
    3
    7
    5
    Dyspnoea
         subjects affected / exposed
    5 / 83 (6.02%)
    3 / 84 (3.57%)
    6 / 78 (7.69%)
         occurrences all number
    5
    3
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 83 (15.66%)
    10 / 84 (11.90%)
    3 / 78 (3.85%)
         occurrences all number
    20
    10
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 84 (0.00%)
    4 / 78 (5.13%)
         occurrences all number
    2
    0
    4
    Constipation
         subjects affected / exposed
    6 / 83 (7.23%)
    3 / 84 (3.57%)
    6 / 78 (7.69%)
         occurrences all number
    6
    3
    6
    Diarrhoea
         subjects affected / exposed
    10 / 83 (12.05%)
    19 / 84 (22.62%)
    20 / 78 (25.64%)
         occurrences all number
    17
    25
    27
    Nausea
         subjects affected / exposed
    9 / 83 (10.84%)
    10 / 84 (11.90%)
    12 / 78 (15.38%)
         occurrences all number
    12
    11
    13
    Stomatitis
         subjects affected / exposed
    8 / 83 (9.64%)
    4 / 84 (4.76%)
    0 / 78 (0.00%)
         occurrences all number
    9
    5
    0
    Vomiting
         subjects affected / exposed
    6 / 83 (7.23%)
    4 / 84 (4.76%)
    6 / 78 (7.69%)
         occurrences all number
    7
    4
    7
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    68 / 83 (81.93%)
    65 / 84 (77.38%)
    1 / 78 (1.28%)
         occurrences all number
    96
    93
    1
    Dry skin
         subjects affected / exposed
    8 / 83 (9.64%)
    10 / 84 (11.90%)
    1 / 78 (1.28%)
         occurrences all number
    12
    12
    1
    Erythema
         subjects affected / exposed
    16 / 83 (19.28%)
    11 / 84 (13.10%)
    0 / 78 (0.00%)
         occurrences all number
    25
    13
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 84 (1.19%)
    14 / 78 (17.95%)
         occurrences all number
    1
    2
    18
    Photosensitivity reaction
         subjects affected / exposed
    10 / 83 (12.05%)
    4 / 84 (4.76%)
    0 / 78 (0.00%)
         occurrences all number
    16
    5
    0
    Pruritus
         subjects affected / exposed
    33 / 83 (39.76%)
    30 / 84 (35.71%)
    2 / 78 (2.56%)
         occurrences all number
    45
    38
    2
    Rash
         subjects affected / exposed
    7 / 83 (8.43%)
    6 / 84 (7.14%)
    0 / 78 (0.00%)
         occurrences all number
    16
    17
    0
    Skin fissures
         subjects affected / exposed
    14 / 83 (16.87%)
    16 / 84 (19.05%)
    2 / 78 (2.56%)
         occurrences all number
    16
    22
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 83 (6.02%)
    5 / 84 (5.95%)
    7 / 78 (8.97%)
         occurrences all number
    5
    6
    7
    Muscle spasms
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 84 (5.95%)
    1 / 78 (1.28%)
         occurrences all number
    4
    5
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 83 (24.10%)
    9 / 84 (10.71%)
    7 / 78 (8.97%)
         occurrences all number
    23
    9
    9
    Hyperglycaemia
         subjects affected / exposed
    4 / 83 (4.82%)
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    5
    8
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 83 (1.20%)
    5 / 84 (5.95%)
    0 / 78 (0.00%)
         occurrences all number
    1
    6
    0
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 84 (5.95%)
    1 / 78 (1.28%)
         occurrences all number
    3
    11
    1
    Hypocalcaemia
         subjects affected / exposed
    9 / 83 (10.84%)
    8 / 84 (9.52%)
    2 / 78 (2.56%)
         occurrences all number
    13
    10
    2
    Hypokalaemia
         subjects affected / exposed
    10 / 83 (12.05%)
    4 / 84 (4.76%)
    3 / 78 (3.85%)
         occurrences all number
    14
    4
    3
    Hypomagnesaemia
         subjects affected / exposed
    57 / 83 (68.67%)
    47 / 84 (55.95%)
    6 / 78 (7.69%)
         occurrences all number
    84
    72
    9
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    13 / 83 (15.66%)
    8 / 84 (9.52%)
    1 / 78 (1.28%)
         occurrences all number
    21
    10
    1
    Paronychia
         subjects affected / exposed
    15 / 83 (18.07%)
    18 / 84 (21.43%)
    3 / 78 (3.85%)
         occurrences all number
    22
    20
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 83 (1.20%)
    5 / 84 (5.95%)
    0 / 78 (0.00%)
         occurrences all number
    1
    6
    0
    Urinary tract infection
         subjects affected / exposed
    5 / 83 (6.02%)
    3 / 84 (3.57%)
    1 / 78 (1.28%)
         occurrences all number
    5
    3
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    Amendment 1: Extended the planned end of trial date. Added pregnancy testing during screening and treatment periods. Revised the IDMC meeting frequency and responsibilities. Removed stratification by intended treatment (Best Supportive Care vs. active anticancer treatment) and required subjects to be randomized in the ratio of 1:1:1 to Sym004 Arms A and B and the control group. Removed biweekly dosage and the option for an 18 mg/kg dose per application (i.e., dose). Added subject monitoring for 1 hour post-infusion. Revised dose reduction rules/added dose reduction for Sym004-induced reactions (rash, xerosis, paronychia, pruritus, and photosensitivity). Removed tumor node metastases staging at trial entry.
    13 Mar 2015
    Amendment 2: Updated sponsor and medical monitor information.
    27 Jan 2016
    Amendment 3: Updated the definition of end of trial, extended the trial minimum survival follow-up, and updated the primary endpoint statistical analysis. Clarified the subject weight to be used for trial drug administration and the use of low potency steroid creams. Further detailed the process for receipt of trial treatment by the Investigator. Clarified when the End of Treatment Visit was performed.
    25 Oct 2016
    Amendment 4: Updated biomarkers to be evaluated and clarified the reduction of data collection after the primary analysis was performed.

    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.
    Considering the hypothesis-generating nature of a phase 2 clinical trial, the intent-to-treat (ITT) analysis should be viewed as the starting point of a scientific investigation process, not the final conclusion.
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