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    Clinical Trial Results:
    An Open-label, Multi-Center Phase 1b/2a Trial Investigating Different Doses of Sym004 in Combination with FOLFIRI in Patients with Metastatic Colorectal Cancer Progressing after First-Line Therapy

    Summary
    EudraCT number
    2015-003047-19
    Trial protocol
    ES  
    Global end of trial date
    05 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Mar 2019
    First version publication date
    30 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Sym004-09
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02568046
    WHO universal trial number (UTN)
    -
    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
    15 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary Objective of Dose-Escalation Phase (Phase 1b): To determine the MTD and RP2D of Sym004 when administered by intravenous (IV) infusion every second week in combination with a standard dosing regimen of FOLFIRI to patients with locally advanced or metastatic colorectal cancer (CRC). Primary Objective of Dose-Expansion Phase (Phase 2a): To evaluate the antineoplastic effect of Sym004 when administered at the RP2D in combination with FOLFIRI to patients with locally advanced or metastatic CRC. In January 2017, the trial was terminated during Phase 1b and enrollment was prematurely discontinued. The primary objective changed to assess the safety of the treatment combination; collection of data for secondary and exploratory objectives was omitted.
    Protection of trial subjects
    The potential to slow infusions, interrupt dosing, decrease the doses administered, and to discontinue administration of Sym004 in the event of specific AEs was outlined. In addition, steps to prevent infusion reactions and measures to intervene in the event of electrolyte imbalances and cutaneous toxicities were specified. Furthermore, prophylactic treatment for FOLFIRI-induced diarrhea and vomiting according to institutional standards was required. Sym004 infusions were administered under the close supervision of an experienced physician in an environment where full resuscitation facilities were immediately available. At the end of each infusion, the IV line remained in place for at least 1 hour to allow administration of IV drugs, if necessary. Patients were carefully observed for a minimum of 2 hours following completion of the first administration of Sym004 and a minimum of 1 hour following completion of subsequent administrations.
    Background therapy
    All patients received a standard dosing regimen of FOLFIRI. The standard regimen consists of Irinotecan (180 mg/m^2 IV, infused over 60-90 minutes) concurrently with Folinic Acid (400 mg/m^2 IV, infused over 120 minutes) followed by 5-FU (400 mg/m^2 IV bolus, then 2400 mg/m^2 infused over 46 hours).
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Mar 2016
    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
    Spain: 5
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    10
    EEA total number of subjects
    5
    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)
    5
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first patient was enrolled in March 2016. In January 2017, the trial was terminated early and enrollment was prematurely discontinued.

    Pre-assignment
    Screening details
    Male or female, 18 years of age at the time of informed consent. ECOG PS of 0 or 1. Histologically or cytologically confirmed, locally advanced or metastatic CRC documented to be without KRAS or NRAS gene mutations. Failed treatment for locally advanced or metastatic disease. Eligible for FOLFIRI. Measurable disease according to RECIST v1.1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sym004, 12 mg/kg + FOLFIRI
    Arm description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)
    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 diluted in saline in an infusion bag prior to administration. The infusion had to be completed within 12 hours of preparation of the infusion bag. All patients were given IV infusions of Sym004, administered every second week (Day 1 and Day 15 of each 28 day cycle ±2 days) through a peripheral line or indwelling catheter, and with the use of an infusion pump and an inline filter. Sym004 was dosed according to body weight. The allocated dose level was confirmed in writing by Sponsor or designee on an allocation form.

    Arm title
    Sym004, 9 mg/kg + FOLFIRI
    Arm description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)
    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 diluted in saline in an infusion bag prior to administration. The infusion had to be completed within 12 hours of preparation of the infusion bag. All patients were given IV infusions of Sym004, administered every second week (Day 1 and Day 15 of each 28 day cycle ±2 days) through a peripheral line or indwelling catheter, and with the use of an infusion pump and an inline filter. Sym004 was dosed according to body weight. The allocated dose level was confirmed in writing by Sponsor or designee on an allocation form.

    Number of subjects in period 1
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI
    Started
    5
    5
    Completed
    5
    5
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sym004, 12 mg/kg + FOLFIRI
    Arm description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)
    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 diluted in saline in an infusion bag prior to administration. The infusion had to be completed within 12 hours of preparation of the infusion bag. All patients were given IV infusions of Sym004, administered every second week (Day 1 and Day 15 of each 28 day cycle ±2 days) through a peripheral line or indwelling catheter, and with the use of an infusion pump and an inline filter. Sym004 was dosed according to body weight. The allocated dose level was confirmed in writing by Sponsor or designee on an allocation form.

    Arm title
    Sym004, 9 mg/kg + FOLFIRI
    Arm description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)
    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 diluted in saline in an infusion bag prior to administration. The infusion had to be completed within 12 hours of preparation of the infusion bag. All patients were given IV infusions of Sym004, administered every second week (Day 1 and Day 15 of each 28 day cycle ±2 days) through a peripheral line or indwelling catheter, and with the use of an infusion pump and an inline filter. Sym004 was dosed according to body weight. The allocated dose level was confirmed in writing by Sponsor or designee on an allocation form.

    Number of subjects in period 2
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI
    Started
    5
    5
    Completed
    0
    2
    Not completed
    5
    3
         Progressive disease
    1
    -
         Death
    2
    -
         Other event
    -
    1
         Adverse event, non-fatal
    -
    1
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sym004, 12 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Reporting group title
    Sym004, 9 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Reporting group values
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI Total
    Number of subjects
    5 5 10
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    1 4 5
        From 65-84 years
    4 1 5
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.3 ± 8.55 61.1 ± 9.95 -
    Gender categorical
    Units: Subjects
        Female
    2 2 4
        Male
    3 3 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 2 3
        Not Hispanic or Latino
    4 3 7
        Unknown or Not Responded
    0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    5 5 10
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Region of Enrollment
    Units: Subjects
        United States
    3 2 5
        Spain
    2 3 5
    Height
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    170.4 ± 8.57 171.3 ± 4.47 -
    Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    76.6 ± 11.97 82.5 ± 16.10 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.5 ± 4.20 28.0 ± 4.52 -
    Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    1.9 ± 0.17 2.0 ± 0.24 -

    End points

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    End points reporting groups
    Reporting group title
    Sym004, 12 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Reporting group title
    Sym004, 9 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)
    Reporting group title
    Sym004, 12 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Reporting group title
    Sym004, 9 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 non-overlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Primary: Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence Measured From Baseline to End of Trial Participation, as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03).

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    End point title
    Number of Participants With Adverse Events (AEs) by Nature, Severity, and Occurrence Measured From Baseline to End of Trial Participation, as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03). [1]
    End point description
    AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. The incidence and type of AEs (e.g., treatment-emergent AE [TEAE]) were summarized according to MedDRA system organ classes and preferred terms. An AE was considered as treatment-emergent if it occurred after the first treatment administration. All safety analyses were conducted using the Full Analysis Set (FAS) population, defined as all patients who received at least 1 dose of trial treatment.
    End point type
    Primary
    End point timeframe
    15 Months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Because the trial was discontinued prematurely for business reasons, no formal efficacy analyses were conducted.
    End point values
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI
    Number of subjects analysed
    5
    5
    Units: Participants
        At least 1 TEAE
    5
    5
        At least 1 Serious TEAE
    3
    2
        At least 1 Serious TEAE related to Sym004 only
    0
    0
        At least 1 TEAE leading to Sym004 dose reduction
    1
    2
        At least 1 TEAE leading to interruption of Sym004
    3
    5
        At least 1 TEAE leading to Sym004 withdrawl
    2
    2
        At least 1 TEAE leading to FOLFIRI withdrawl
    1
    2
        At least 1 TEAE leading to trial termination
    0
    1
        At least 1 TEAE related to Sym004 + FOLFIRI
    4
    3
        At least 1 TEAE related to Sym004 only
    4
    5
        At least 1 TEAE related to FOLFIRI only
    4
    4
        At least 1 TEAE Grade ≥3 related to Sym004+FOLFIRI
    2
    2
        At least 1 TEAE Grade ≥3 related to Sym004 only
    0
    2
        At least 1 TEAE Grade ≥3 related to FOLFIRI only
    1
    1
        At least 1 dermatologic toxicity
    3
    5
        At least 1 TEAE of hypomagnesaemia
    3
    0
        At least 1 infusion related reaction TEAE
    3
    3
        At least 1 TEAE resulting in death
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event data collection period was 15 months.
    Adverse event reporting additional description
    AEs were collected from the signing of informed consent and continued 1 month (i.e., at least 28 days) after the last administration of treatment (i.e., after both Sym004 and FOLFIRI were discontinued). After the decision was made to prematurely discontinue the trial, collection of AEs continued 1 month after the last administration of Sym004.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sym004, 12 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level 1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 nonoverlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Reporting group title
    Sym004, 9 mg/kg + FOLFIRI
    Reporting group description
    Phase 1b, Dose-Escalation: Dose Level -1 IMP: Sym004, a 1:1 mixture of 2 monoclonal antibodies (mAbs) which bind specifically to 2 nonoverlapping epitopes of the epidermal growth factor receptor (EGFR). Background Therapy: FOLFIRI (standard regimen)

    Serious adverse events
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 5 (40.00%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Sym004, 12 mg/kg + FOLFIRI Sym004, 9 mg/kg + FOLFIRI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    5 / 5 (100.00%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    3
    Chest discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    4 / 5 (80.00%)
    2 / 5 (40.00%)
         occurrences all number
    4
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 5 (60.00%)
         occurrences all number
    4
    3
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Lipase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Weight increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 5 (80.00%)
         occurrences all number
    1
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Nasal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Aphasia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    2
    Syncope
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Ascites
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Chapped lips
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Cheilitis
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 5 (40.00%)
         occurrences all number
    6
    3
    Dry mouth
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    Odynophagia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Oral pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 5 (40.00%)
         occurrences all number
    4
    3
    Vomiting
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 5 (60.00%)
         occurrences all number
    2
    3
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 5 (40.00%)
    5 / 5 (100.00%)
         occurrences all number
    2
    5
    Dermatitis allergic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Skin toxicity
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 5 (0.00%)
         occurrences all number
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Hypovolaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2015
    1. Increased the blood volume collected for the biomarker samples. A larger volume of blood, and subsequent plasma, was needed for biomarker analysis when using Next-Generation Sequencing (NGS). 2. Timing for collection of AEs and SAEs was extended to allow total safety surveillance to include analysis of unanticipated problems having to do with overall trial conduct. This would include any adverse effects that may occur from protocol-specific investigations at screening.
    05 Aug 2016
    1. Added additional dose levels to facilitate further exploration of the safety and tolerability of Sym004. 2. Initiated mandatory prophylaxis for diarrhea in Cycle 1 with potential to continue in later cohorts. 3. Modified the inclusion and exclusion criteria section to allow enrollment of patients who progressed > 3 months after last dose and to allow enrollment of patients treated with drugs that potentially could cause QT prolongation. 4. Removed Sym004 dose-adjustment for obese patients. 5. Clarification of biomarker testing from collected tumor biopsies and revision of the tumor marker section to only collect CEA. 6. Modified the statistical section to clarify the number of patients required and added relevant references. 7. Specified grading of adverse events when there are changes in severity.
    22 Feb 2017
    1. Explanation included for prematurely discontinuing trial enrollment. 2. Changed the visit schedule for treatment and follow-up to apply only until Sym004 has been discontinued. 3. Omitted collection of non-safety related assessments and modified the statistical section to further reduce the collection of data to information needed for safety reporting required by authorities. 4. Revised the AE/SAE reporting requirements for progression of disease.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Jan 2017
    The trial was terminated prematurely as development of Sym004 in combination with FOLFIRI was discontinued.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was terminated as development of Sym004 in combination with FOLFIRI was discontinued. The primary objective changed to assess the safety of the treatment combination; collection of data for secondary and exploratory objectives was omitted.
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