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    Clinical Trial Results:
    A Phase I/IIa study of TG6002 (VV TK-RR-FCU1) administered by intravenous (IV) infusions in combination with oral flucytosine (5-FC) in patients with advanced gastro-intestinal (GI) tumors

    Summary
    EudraCT number
    		 2018-000039-28
    Trial protocol
    		 FR   BE   ES  
    Global end of trial date
    23 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TG6002.02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03724071
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TRANSGENE S.A.
    Sponsor organisation address
    400 boulevard Gonthier d’Andernach - Parc d’innovation – CS80166, Illkirch-Graffenstaden, France, 67405
    Public contact
    Medical Affairs, TRANSGENE S.A., 33 388279155, clinical.trials@transgene.fr
    Scientific contact
    Medical Affairs, TRANSGENE S.A., 33 388279155, clinical.trials@transgene.fr
    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
    06 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the phase I part is to determine the optimal scheme of administration and the recommended Phase II dose (RP2D) for TG6002 administered as multiple intravenous (IV) infusions in combination with flucytosine (5-FC) in patients with advanced GI tumors. Secondary objectives include the assessessment of the safety and tolerability of multiple TG6002 infusions at escalating doses and determination of the Maximum Tolerated Dose (MTD), if any, of two schemes of administration of TG6002 combined with oral 5-FC.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Regulatory reason
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Spain: 28
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    27
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First participant signed informed consent form on 10 October 2018. Last participant last visit occurred on 30 May 2022, before long term follow-up.

    Pre-assignment
    Screening details
    		 Of 65 screened participants, 51 were included in the trial (35 patients in Arm A and 16 patients in Arm B) and 14 patients were excluded (13 because they were ineligible and 1 declined to participate).

    Period 1
    Period 1 title
    Overall study (overall period, phase I)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Cohorts of 3-6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E6 to 3 x 10E9 pfu every week for 3 weeks in combination with oral 5-FC at the dose of 200 mg/kg/day for 16 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    TG6002
    Investigational medicinal product code
    TG6002
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered at dose levels of TG6002 ranging from 1 x 10E6 to 3 x 10E9 pfu by IV infusion every week for 3 weeks (D1 / D8 / D15)

    Investigational medicinal product name
    5-FC
    Investigational medicinal product code
    Other name
    Ancotil
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were given the total dose of 200 mg/kg/day of oral 5-FC (split in 4 daily intakes) from Day 5 to 7, Day 12 to 14 and Day 19 to 28.

    Arm title
    		 Arm B
    Arm description
    		 Cohorts of 6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E9 to 3 x 10E9 pfu on Day 1, 3 and 5 in combination with oral 5-FC at the dose of 200 mg/kg/day for 10 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    TG6002
    Investigational medicinal product code
    TG6002
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were administered at dose levels of TG6002 ranging from 1 x 10E9 to 3 x 10E9 pfu by IV infusion on D1, D3 and D5

    Investigational medicinal product name
    5-FC
    Investigational medicinal product code
    Other name
    Ancotil
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were given the total dose of 200 mg/kg/day of oral 5-FC (split in 4 daily intakes) from Day 9 to 18 .

    Number of subjects in period 1
    		Arm A Arm B
    Started
    35
    16
    Completed
    33
    12
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    1
         Clinical situation (ECOG 4 in a context of PD)
    -
    1
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Cohorts of 3-6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E6 to 3 x 10E9 pfu every week for 3 weeks in combination with oral 5-FC at the dose of 200 mg/kg/day for 16 days

    Reporting group title
    Arm B
    Reporting group description
    		 Cohorts of 6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E9 to 3 x 10E9 pfu on Day 1, 3 and 5 in combination with oral 5-FC at the dose of 200 mg/kg/day for 10 days

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 35 16 51
    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)
    		 19 8 27
        From 65-84 years
    		 16 8 24
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (46 to 76) 64 (32 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11 22
        Male
    		 24 5 29
    ECOG performance status
    Units: Subjects
        Score 0
    		 19 6 25
        Score 1
    		 16 10 26
        Score 2
    		 0 0 0
        Score 3
    		 0 0 0
        Score 4
    		 0 0 0
    Tumor stage at initial diagnosis
    Units: Subjects
        Stage IA
    		 2 0 2
        Stage IB
    		 1 0 1
        Stage IIA
    		 1 2 3
        Stage IIB
    		 5 1 6
        Stage IIIA
    		 0 2 2
        Stage IIIB
    		 4 0 4
        Stage IIIC
    		 0 1 1
        Stage IV
    		 22 10 32
    Primary location of disease
    Units: Subjects
        Colon
    		 14 6 20
        Esophagus
    		 1 1 2
        Pancreas
    		 8 6 14
        Rectum
    		 4 1 5
        Stomach
    		 2 0 2
        Other GI location
    		 6 2 8

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Cohorts of 3-6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E6 to 3 x 10E9 pfu every week for 3 weeks in combination with oral 5-FC at the dose of 200 mg/kg/day for 16 days

    Reporting group title
    Arm B
    Reporting group description
    		 Cohorts of 6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E9 to 3 x 10E9 pfu on Day 1, 3 and 5 in combination with oral 5-FC at the dose of 200 mg/kg/day for 10 days

    Primary: Safety and tolerability of TG6002 and 5-FC

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    End point title
    		 Safety and tolerability of TG6002 and 5-FC [1]
    End point description
    Patients were assessed for dose limiting toxicities (DLT) as well as for safety and tolerability of the treatment. A DLT was defined as any of the following treatment-related AEs occurring during the DLT period [Day 1 to Day 28]: any grade 4 toxicity (except isolated Grade 4 lymphopenia lasting ≤ 7 days), grade 3 hypotension or allergic reaction/hypersensitivity, grade 3 skin lesions: ulcerative dermatitis or skin changes with pain interfering with function, at least 10 disseminated pustular lesions, laboratory grade 3 non-hematologic toxicity persisting for >7 days except an increase in AST and/or ALT (>5x ULN), which may last >7 days if total bilirubin is normal or grade 1, drug-induced liver injury fulfilling the criteria of the Hy’s law, grade 3 hematologic toxicity persisting for > 7 days, myocardial infarction or myocarditis, disseminated intravascular coagulation.
    End point type
    Primary
    End point timeframe
    Patients were assessed for dose limiting toxicity (DLTs) occurring within 28 days of administration of the first TG6002 infusion.
    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: Data for this end point were analyzed descriptively.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    35
    16
    Units: Events
        Dose Limiting Toxicities (DLTs)
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (and serious adverse events) were recorded from the first study treatment administration up to 28 days after the last administration of study treatment. SAE related to study treatment were recorded with no time limitation.
    Adverse event reporting additional description
    Adverse event information was collected by regular investigator assessment and regular laboratory testing.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Cohorts of 3-6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E6 to 3 x 10E9 pfu every week for 3 weeks in combination with oral 5-FC at the dose of 200 mg/kg/day for 16 days

    Reporting group title
    Arm B
    Reporting group description
    		 Cohorts of 6 patients administered with TG6002 IV infusion at dose levels ranging from 1 x 10E9 to 3 x 10E9 pfu on Day 1, 3 and 5 in combination with oral 5-FC at the dose of 200 mg/kg/day for 10 days

    Reporting group title
    Safety population
    Reporting group description
    		 Participants who received at least one dose of either study drug

    Serious adverse events
    		 Arm A Arm B Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 35 (51.43%)
    6 / 16 (37.50%)
    24 / 51 (47.06%)
         number of deaths (all causes)
    32
    12
    44
         number of deaths resulting from adverse events
    2
    0
    2
    Investigations
    Fibrin D dimer increased
    Additional description: Fibrin D dimer increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
    Additional description: Cancer pain
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
    Additional description: Tumour pain
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 16 (12.50%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
    Additional description: Spinal cord compression
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
    Additional description: Cognitive disorder
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
    Additional description: Disease progression
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
    Additional description: Large intestinal obstruction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
    Additional description: Small intestinal haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
    Additional description: Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
    Additional description: Dysphagia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
    Additional description: Hepatic function abnormal
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
    Additional description: Hepatitis acute
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
    Additional description: Hyperbilirubinaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
    Additional description: Drug-induced liver injury
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Pulmonary embolism
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: Pneumothorax
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
    Additional description: Urinary tract obstruction
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Liver abscess
    Additional description: Liver abscess
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
    Additional description: Device related infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
    Additional description: Device related sepsis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    Additional description: Septic shock
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Staphylococcal infection
    Additional description: Staphylococcal infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 16 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 35 (97.14%)
    16 / 16 (100.00%)
    50 / 51 (98.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
    Additional description: Tumour pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Vascular disorders
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    8 / 35 (22.86%)
    7 / 16 (43.75%)
    15 / 51 (29.41%)
         occurrences all number
    20
    10
    30
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    5 / 35 (14.29%)
    5 / 16 (31.25%)
    10 / 51 (19.61%)
         occurrences all number
    8
    7
    15
    General disorders and administration site conditions
    Chills
    Additional description: Chills
         subjects affected / exposed
    14 / 35 (40.00%)
    8 / 16 (50.00%)
    22 / 51 (43.14%)
         occurrences all number
    32
    19
    51
    Face oedema
    Additional description: Face oedema
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    19 / 35 (54.29%)
    7 / 16 (43.75%)
    26 / 51 (50.98%)
         occurrences all number
    24
    9
    33
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 16 (25.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    4
    4
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Performance status decreased
    Additional description: Performance status decreased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    24 / 35 (68.57%)
    16 / 16 (100.00%)
    40 / 51 (78.43%)
         occurrences all number
    56
    30
    86
    Reproductive system and breast disorders
    Pelvic discomfort
    Additional description: Pelvic discomfort
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Tonsillar ulcer
    Additional description: Tonsillar ulcer
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Pleuritic pain
    Additional description: Pleuritic pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Oropharyngeal discomfort
    Additional description: Oropharyngeal discomfort
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Hypoxia
    Additional description: Hypoxia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Haemoptysis
    Additional description: Haemoptysis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    6 / 35 (17.14%)
    0 / 16 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    6
    0
    6
    Dysphonia
    Additional description: Dysphonia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Cough
    Additional description: Cough
         subjects affected / exposed
    5 / 35 (14.29%)
    2 / 16 (12.50%)
    7 / 51 (13.73%)
         occurrences all number
    5
    2
    7
    Psychiatric disorders
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    3
    Anxiety
    Additional description: Anxiety
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Investigations
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 16 (18.75%)
    4 / 51 (7.84%)
         occurrences all number
    1
    3
    4
    Amylase increased
    Additional description: Amylase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 16 (25.00%)
    7 / 51 (13.73%)
         occurrences all number
    3
    4
    7
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 16 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    4
    0
    4
    Lipase increased
    Additional description: Lipase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 16 (0.00%)
    5 / 51 (9.80%)
         occurrences all number
    6
    0
    6
    Injury, poisoning and procedural complications
    Procedural pain
    Additional description: Procedural pain
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    2
    1
    3
    Cardiac disorders
    Tachycardia
    Additional description: Tachycardia
         subjects affected / exposed
    4 / 35 (11.43%)
    3 / 16 (18.75%)
    7 / 51 (13.73%)
         occurrences all number
    8
    5
    13
    Sinus tachycardia
    Additional description: Sinus tachycardia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 16 (12.50%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    2
    Nervous system disorders
    Headache
    Additional description: Headache
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 16 (18.75%)
    6 / 51 (11.76%)
         occurrences all number
    5
    5
    10
    Dysgeusia
    Additional description: Dysgeusia
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 16 (18.75%)
    4 / 51 (7.84%)
         occurrences all number
    1
    3
    4
    Dizziness
    Additional description: Dizziness
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Blood and lymphatic system disorders
    Lymphopenia
    Additional description: Lymphopenia
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 16 (43.75%)
    8 / 51 (15.69%)
         occurrences all number
    1
    8
    9
    Leukocytosis
    Additional description: Leukocytosis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Coagulopathy
    Additional description: Coagulopathy
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    7 / 35 (20.00%)
    5 / 16 (31.25%)
    12 / 51 (23.53%)
         occurrences all number
    7
    6
    13
    Thrombocytopenia
    Additional description: Thrombocytopenia
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 16 (18.75%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    3
    Gastrointestinal disorders
    Aphthous ulcer
    Additional description: Aphthous ulcer
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 16 (12.50%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    2
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    7 / 35 (20.00%)
    5 / 16 (31.25%)
    12 / 51 (23.53%)
         occurrences all number
    9
    6
    15
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 16 (6.25%)
    5 / 51 (9.80%)
         occurrences all number
    5
    1
    6
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    11 / 35 (31.43%)
    3 / 16 (18.75%)
    14 / 51 (27.45%)
         occurrences all number
    13
    5
    18
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    15 / 35 (42.86%)
    5 / 16 (31.25%)
    20 / 51 (39.22%)
         occurrences all number
    18
    6
    24
    Large intestinal obstruction
    Additional description: Large intestinal obstruction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Gingival discomfort
    Additional description: Gingival discomfort
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 16 (12.50%)
    4 / 51 (7.84%)
         occurrences all number
    2
    2
    4
    Flatulence
    Additional description: Flatulence
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    5 / 35 (14.29%)
    1 / 16 (6.25%)
    6 / 51 (11.76%)
         occurrences all number
    5
    1
    6
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    12 / 35 (34.29%)
    5 / 16 (31.25%)
    17 / 51 (33.33%)
         occurrences all number
    16
    11
    27
    Hepatobiliary disorders
    Hepatitis
    Additional description: Hepatitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Hyperbilirubinaemia
    Additional description: Hyperbilirubinaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Hypertransaminasaemia
    Additional description: Hypertransaminasaemia
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 16 (12.50%)
    5 / 51 (9.80%)
         occurrences all number
    3
    2
    5
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
    Additional description: Rash maculo-papular
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Rash erythematous
    Additional description: Rash erythematous
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 16 (12.50%)
    4 / 51 (7.84%)
         occurrences all number
    2
    2
    4
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 16 (12.50%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    5
    Decubitus ulcer
    Additional description: Decubitus ulcer
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Skin lesion
    Additional description: Skin lesion
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Sacral pain
    Additional description: Sacral pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Musculoskeletal pain
    Additional description: Musculoskeletal pain
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    4 / 35 (11.43%)
    0 / 16 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    4
    0
    4
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 16 (6.25%)
    5 / 51 (9.80%)
         occurrences all number
    4
    1
    5
    Infections and infestations
    Bronchitis
    Additional description: Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Genital herpes
    Additional description: Genital herpes
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Gingivitis
    Additional description: Gingivitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Oral candidiasis
    Additional description: Oral candidiasis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Rash pustular
    Additional description: Rash pustular
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 16 (18.75%)
    4 / 51 (7.84%)
         occurrences all number
    1
    3
    4
    Rhinitis
    Additional description: Rhinitis
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 16 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    2
    0
    2
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Metabolism and nutrition disorders
    Hypophosphataemia
    Additional description: Hypophosphataemia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 16 (12.50%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    2
    Hyponatraemia
    Additional description: Hyponatraemia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Hypokalaemia
    Additional description: Hypokalaemia
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 16 (6.25%)
    3 / 51 (5.88%)
         occurrences all number
    2
    1
    3
    Hypocalcaemia
    Additional description: Hypocalcaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 16 (6.25%)
    2 / 51 (3.92%)
         occurrences all number
    1
    1
    2
    Hypoalbuminaemia
    Additional description: Hypoalbuminaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 16 (6.25%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    1
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    9 / 35 (25.71%)
    5 / 16 (31.25%)
    14 / 51 (27.45%)
         occurrences all number
    9
    6
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2018
    Protocol V3.0 dated 15-Jun-2018 : addition of an eligibility criteria (patients must have been previously exposed to fluoropyrimidine-based chemotherapy) and revision of a DLT criterion (in order to delete the exclusion of Grade 3 Flu-like symptoms).
    25 Jul 2019
    Protocol V5.0 dated 25-Jul-2019: add a 5th cohort (with a TG6002 dose of 1x109 pfu), add a biopsy on Day 5, update eligibility criteria (biopsies of tumor metastatic lesions are to be performed in all patients from 3 x10E8 pfu cohort, and non-active inflammatory bowel disease is no longer considered as an exclusion criterion), add the collection of archival serum and plasma samples on Day 5, to add the severe Drug-induced liver injury as a DLT and to prolong the screening period from 14 to 28 days.
    12 Nov 2020
    Protocol V9.0 dated 12-Nov-2020: add the arm B with a new administration scheme (TG6002 infusion on Day 1, Day 3, and Day 5 and 5-FC intakes during 10 consecutive days from Day 9 to Day 18 in arm B) and 4 cohorts (from 1x10E9 to 1x10E10) and adapt the sampling and exams timepoints accordingly. Changes were implemented to the initial arm A: remove the 24h timepoint for PK analysis and add the 1h hour timepoint, for humoral immune response (anti-VV) and neutralizing antibodies add a timepoint on Day 7 and on Day 14, for PBMC remove the Day 28 timepoint and add the Day 43 timepoint.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Feb 2023
    The trial was prematurely terminated per Sponsor decision on 23 February 2023 after the completion of the phase I portion and before the commencement of the phase II, for reasons other than safety.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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