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    Clinical Trial Results:
    A phase I/IIa trial to evaluate the safety and efficacy of the combination of the oncolytic immunotherapy Pexa-Vec with the PD-1 receptor blocking antibody nivolumab in the first-line treatment of advanced hepatocellular carcinoma (HCC)

    Summary
    EudraCT number
    		 2016-000085-32
    Trial protocol
    		 IT  
    Global end of trial date
    03 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2021
    First version publication date
    22 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TG6006.01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03071094
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TRANSGENE
    Sponsor organisation address
    400 boulevard Gonthier d'Andernach, CS80166, Parc d'Innovation, Illkirch-Graffenstaden, France, 67405
    Public contact
    Medical Affairs Secretariat, TRANSGENE, 33 388279155, clinical.trials@transgene.fr
    Scientific contact
    Associate Medical Director, TRANSGENE, 33 388279100, 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
    30 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase I part: To evaluate the safety profile of intratumoral (IT) Pexa-Vec combined with intravenous (IV) nivolumab in patients with advanced HCC. Phase IIa part: To evaluate the anti-tumor activity and efficacy of IT Pexa-Vec combined with IV nivolumab in patients with advanced hepatocellular carcinoma (HCC) with respect to Overall Response Rate (ORR) (RECIST 1.1).
    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
    04 Jul 2017
    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
    France: 11
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First participant signed informed consent on 04 July 2017. Last participant last visit occurred on 03 February 2021.

    Pre-assignment
    Screening details
    		 Of 14 screened participants, 12 were included in the trial (one subject did not fulfill all eligibility criteria and one subject could not be included due to study early termination).

    Pre-assignment period milestones
    Number of subjects started
    		 14
    Number of subjects completed
    		 12

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Subject did not fulfill all eligibility criteria: 1
    Reason: Number of subjects
    		 Study terminated early by the Sponsor: 1
    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pexa-Vec combined with nivolumab - Phase I
    Arm description
    		 Phase I part of the trial: single cohort of 6 patients assessing the safety of standard Pexa-Vec and nivolumab doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexastimogene devacirepvec
    Investigational medicinal product code
    Pexa-Vec
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    Participants were administered Pexa-Vec as 3 bi-weekly intratumoral (IT) injections of 10e9 plaque-forming units (pfu) at day 1, week 2 and week 4.

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered 240 mg of nivolumab intravenously every 2 weeks (from week 2).

    Arm title
    		 Pexa-Vec combined with nivolumab - Phase IIa
    Arm description
    		 Phase IIa part of the trial: extension of the Phase I part to up to 30 patients, assessing the efficacy and safety of Pexa-Vec and nivolumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pexastimogene devacirepvec
    Investigational medicinal product code
    Pexa-Vec
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    Participants were administered Pexa-Vec as 3 bi-weekly intratumoral (IT) injections of 10e9 plaque-forming units (pfu) at day 1, week 2 and week 4.

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants were administered 240 mg nivolumab intravenously every 2 weeks (from week 2).

    Number of subjects in period 1 [1]
    		Pexa-Vec combined with nivolumab - Phase I Pexa-Vec combined with nivolumab - Phase IIa
    Started
    7
    5
    Completed
    5
    4
    Not completed
    2
    1
         Adverse event, serious fatal
    -
    1
         Disease progression
    1
    -
         Adverse event, non-fatal
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 14 screened participants, 12 were included in the trial (one subject did not fulfill all eligibility criteria and one subject could not be included due to study early termination).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pexa-Vec combined with nivolumab - Phase I
    Reporting group description
    		 Phase I part of the trial: single cohort of 6 patients assessing the safety of standard Pexa-Vec and nivolumab doses.

    Reporting group title
    Pexa-Vec combined with nivolumab - Phase IIa
    Reporting group description
    		 Phase IIa part of the trial: extension of the Phase I part to up to 30 patients, assessing the efficacy and safety of Pexa-Vec and nivolumab.

    Reporting group values
    		 Pexa-Vec combined with nivolumab - Phase I Pexa-Vec combined with nivolumab - Phase IIa Total
    Number of subjects
    		 7 5 12
    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)
    		 2 2 4
        From 65-84 years
    		 5 3 8
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 67.7 ± 8.1 62.8 ± 18.0 -
    Gender categorical
    Units: Subjects
        Female
    		 2 1 3
        Male
    		 5 4 9
    Stage of HCC per BCLC (Barcelona Clinic Liver Cancer)
    Units: Subjects
        Stage 0
    		 0 0 0
        Stage A
    		 0 0 0
        Stage B
    		 0 0 0
        Stage C
    		 7 5 12
        Stage D
    		 0 0 0
    ECOG performance status
    Units: Subjects
        Score 0
    		 4 5 9
        Score 1
    		 3 0 3
        Score 2
    		 0 0 0
        Score 3
    		 0 0 0
        Score 4
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Pexa-Vec combined with nivolumab - Phase I
    Reporting group description
    		 Phase I part of the trial: single cohort of 6 patients assessing the safety of standard Pexa-Vec and nivolumab doses.

    Reporting group title
    Pexa-Vec combined with nivolumab - Phase IIa
    Reporting group description
    		 Phase IIa part of the trial: extension of the Phase I part to up to 30 patients, assessing the efficacy and safety of Pexa-Vec and nivolumab.

    Subject analysis set title
    Safety population (phase I)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received at least one dose of either study drug.

    Subject analysis set title
    DLT (dose-limiting toxicity) population (phase I)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received all 3 Pexa-Vec and 2 nivolumab administrations and completed the 4 weeks from the first study drug administration and/or participants having exhibited a dose-limiting toxicicty (DLT) after at least one dose of either study drug (excluding one patient who did not complete the 4 week-period from the first study drug administration).

    Subject analysis set title
    Safety population (phase I and phase IIa)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received at least one dose of either study drug.

    Subject analysis set title
    Intent to treat population (phase I and phase IIa)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants who received at least one dose of either study drug.

    Primary: Number of participants with dose limiting toxicities (DLTs)

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    End point title
    		 Number of participants with dose limiting toxicities (DLTs) [1]
    End point description
    DLTs are occurrence of any following AE related to study drugs occurring during 4 weeks after 1st Pexa-Vec injection: 1. Grade 3-4 non-hematologic toxicity representing a 2-grade increase over baseline, excluding: nausea, vomiting, diarrhea, fever >40.0°C lasting less than 24h (grade 3), alopecia, grade 3 fatigue* and grade 3 laboratory/metabolic abnormalities* (*returning to grade 2 or less within 72h) 2. Grade ≥ 3 acute immune-related AE involving major organs 3. Grade ≥ 3 injection site reaction 4. AST or ALT ≥ 10xULN unless related to liver metastases progression; AST or ALT doubling concurrent with total bilirubin doubling 5. Any toxicity resulting in treatment delay of 2 or more weeks 6. Grade ≥ 3 or ≥ 2-grade neutropenia increase over baseline lasting >7 days, neutropenic fever, grade 4 thrombocytopenia (or grade 3 with bleeding) 7. Association of LVEF less than LLN, blood troponin T or I increase above ULN and any ECG abnormality indicating grade 3 cardiac disorder.
    End point type
    Primary
    End point timeframe
    4 weeks from the first study drug administration
    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
    		 DLT (dose-limiting toxicity) population (phase I)
    Number of subjects analysed
    6
    Units: Participants
    0
    No statistical analyses for this end point

    Primary: Number of participants with serious adverse events (SAEs)

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    End point title
    		 Number of participants with serious adverse events (SAEs) [2]
    End point description
    A Serious Adverse Event (SAE) is defined as any untoward medical occurrence or effect in a patient, whether or not considered related to the protocol treatment, that at any dose: (i) results in death, (ii) is lifethreatening, (iii) requires inpatient's hospitalization or prolongation of existing inpatients´ hospitalization, (iv) results in persistent or significant disability or incapacity, (v) is a congenital anomaly or birth defect, (vi) results in any other medically important condition.
    End point type
    Primary
    End point timeframe
    4 weeks from the first study drug administration
    Notes
    [2] - 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
    		 Safety population (phase I)
    Number of subjects analysed
    7
    Units: Participants
    6
    No statistical analyses for this end point

    Primary: Overall response rate (ORR) according to RECIST 1.1.

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    End point title
    		 Overall response rate (ORR) according to RECIST 1.1. [3]
    End point description
    Overall Response Rate (ORR): proportion of patients, whose best overall response is either complete response (CR) or partial response (PR), confirmed at least 4 weeks after initial documentation.
    End point type
    Primary
    End point timeframe
    6 months from the first study drug administration
    Notes
    [3] - 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: Efficacy data were analyzed descriptively and presented for phase I + phase IIa.
    End point values
    		 Intent to treat population (phase I and phase IIa)
    Number of subjects analysed
    12
    Units: Percentage of participants
        number (confidence interval 95%)
    33.3 (9.9 to 65.1)
    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 drug administration up to 28 days after the last study drug dose.
    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
    23.1
    Reporting groups
    Reporting group title
    Pexa-Vec combined with nivolumab - Phase I
    Reporting group description
    		 Participants who received at least one dose of either study drug.

    Reporting group title
    Pexa-Vec combined with nivolumab - Phase IIa
    Reporting group description
    		 Participants who received at least one dose of either study drug.

    Reporting group title
    Safety population (phase I and phase IIa)
    Reporting group description
    		 Participants who received at least one dose of either study drug.

    Serious adverse events
    		 Pexa-Vec combined with nivolumab - Phase I Pexa-Vec combined with nivolumab - Phase IIa Safety population (phase I and phase IIa)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    4 / 5 (80.00%)
    10 / 12 (83.33%)
         number of deaths (all causes)
    2
    1
    3
         number of deaths resulting from adverse events
    1
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour necrosis
    Additional description: Tumour necrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
    Additional description: Spinal compression fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: General physical health deterioration
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Inflammation
    Additional description: Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Acute kidney injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         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
    Device related infection
    Additional description: Device related infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         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
    Diabetic ketoacidosis
    Additional description: Diabetic ketoacidosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
    Additional description: Hypercalcaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         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
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pexa-Vec combined with nivolumab - Phase I Pexa-Vec combined with nivolumab - Phase IIa Safety population (phase I and phase IIa)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Haematoma
    Additional description: Haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Hypertension
    Additional description: Hypertension
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 5 (40.00%)
    6 / 12 (50.00%)
         occurrences all number
    6
    8
    14
    Hypotension
    Additional description: Hypotension
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    5
    0
    5
    Peripheral venous disease
    Additional description: Peripheral venous disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 5 (100.00%)
    7 / 12 (58.33%)
         occurrences all number
    2
    6
    8
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Chills
    Additional description: Chills
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    4
    0
    4
    Influenza like illness
    Additional description: Influenza like illness
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 5 (60.00%)
    4 / 12 (33.33%)
         occurrences all number
    3
    5
    8
    Injection site pain
    Additional description: Injection site pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Oedema peripheral
    Additional description: Oedema peripheral
         subjects affected / exposed
    5 / 7 (71.43%)
    0 / 5 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    6
    0
    6
    Pyrexia
    Additional description: Pyrexia
         subjects affected / exposed
    7 / 7 (100.00%)
    1 / 5 (20.00%)
    8 / 12 (66.67%)
         occurrences all number
    16
    1
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    3 / 12 (25.00%)
         occurrences all number
    3
    1
    4
    Dyspnoea
    Additional description: Dyspnoea
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    0
    2
    Epistaxis
    Additional description: Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Nervousness
    Additional description: Nervousness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Investigations
    C-reactive protein
    Additional description: C-reactive protein
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Electrocardiogram QT prolonged
    Additional description: Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Liver function test increased
    Additional description: Liver function test increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Neutrophil count decreased
    Additional description: Neutrophil count decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Transaminases increased
    Additional description: Transaminases increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Troponin I increased
    Additional description: Troponin I increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Weight decreased
    Additional description: Weight decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    White blood cell count increased
    Additional description: White blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Arrhythmia
    Additional description: Arrhythmia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Sinus tachycardia
    Additional description: Sinus tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    4
    1
    5
    Nervous system disorders
    Headache
    Additional description: Headache
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    3
    4
    Hepatic encephalopathy
    Additional description: Hepatic encephalopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Neuropathy peripheral
    Additional description: Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Paraesthesia
    Additional description: Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorders
    Abdominal distension
    Additional description: Abdominal distension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Abdominal pain
    Additional description: Abdominal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    3 / 12 (25.00%)
         occurrences all number
    2
    4
    6
    Abdominal pain upper
    Additional description: Abdominal pain upper
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    3
    4
    Ascites
    Additional description: Ascites
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    3 / 12 (25.00%)
         occurrences all number
    4
    1
    5
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    4
    0
    4
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 5 (40.00%)
    4 / 12 (33.33%)
         occurrences all number
    2
    2
    4
    Dry mouth
    Additional description: Dry mouth
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Haemorrhoids
    Additional description: Haemorrhoids
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    3
    Hiatus hernia
    Additional description: Hiatus hernia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Melaena
    Additional description: Melaena
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    4
    5
    Oesophagitis
    Additional description: Oesophagitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Stomatitis
    Additional description: Stomatitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Toothache
    Additional description: Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Vomiting
    Additional description: Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    2
    3
    Skin and subcutaneous tissue disorders
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 5 (20.00%)
    4 / 12 (33.33%)
         occurrences all number
    7
    1
    8
    Rash
    Additional description: Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Rash erythematous
    Additional description: Rash erythematous
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Skin mass
    Additional description: Skin mass
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Renal and urinary disorders
    Renal failure
    Additional description: Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Renal impairment
    Additional description: Renal impairment
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    2
    Strangury
    Additional description: Strangury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    4
    Back pain
    Additional description: Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 5 (40.00%)
    3 / 12 (25.00%)
         occurrences all number
    1
    2
    3
    Myalgia
    Additional description: Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Pain in extremity
    Additional description: Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Spinal pain
    Additional description: Spinal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Fungal infection
    Additional description: Fungal infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    3
    0
    3
    Rash pustular
    Additional description: Rash pustular
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 5 (40.00%)
    5 / 12 (41.67%)
         occurrences all number
    3
    2
    5
    Tooth infection
    Additional description: Tooth infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Urinary tract infection
    Additional description: Urinary tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
    Additional description: Decreased appetite
         subjects affected / exposed
    5 / 7 (71.43%)
    2 / 5 (40.00%)
    7 / 12 (58.33%)
         occurrences all number
    6
    2
    8
    Diabetes mellitus
    Additional description: Diabetes mellitus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Hypomagnesaemia
    Additional description: Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Type 2 diabetes mellitus
    Additional description: Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2017
    Protocol amendment 1 dated 26 June 2017: reinforcement of the cardiac monitoring with addition of cardiac echography, electrocardiogram and measurement of blood troponin T or I levels at baseline and at various timepoints after Pexa-Vec/nivolumab administrations. Cardiac toxicities were added to the list of dose-limiting toxicities (DLT).
    19 Oct 2017
    Protocol amendment 2 dated 19 October 2017: introduction of a clearance for study participation after a cardiology consultation and increase of the frequency of the cardiac echography, electrocardiogram and measurements of blood troponin T or I levels. Change in the prophylactic antipyretic medication by introduction of intakes of oral ibuprofen alternating with paracetamol. Addition of the prophylactic antiemetic medication with esomeprazole.
    22 Dec 2017
    Protocol amendment 3 dated 22 December 2017: introduction of the ability to temporarily suspend concomitant anti-hypertensive medications in case of hypertension. Precision that ibuprofen may be contra-indicated in case of underlying advanced cirrhosis. Exclusion of grade 3 fever from the dose limiting toxicities. Precision of the severity (grade ≥ 3) in the definition of the DLT neutropenia.
    04 May 2018
    Protocol amendment 4 dated 04 May 2018: additional contact for reporting serious adverse events (SAE), pregnancy and overdose.
    20 Mar 2019
    Protocol amendment 5 dated 20 March 2019: no substantial changes introduced, only administrative changes and re-phrasings for sake of clarity.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Sep 2019
    The trial was terminated prematurely during the Phase IIa due to the failure of Pexa-Vec and nivolumab in their respective pivotal trials in HCC.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early as per Sponsor's decision based on the failure of Pexa-Vec and nivolumab in their respective pivotal trials in HCC. Consequently, the enrollment in Phase IIa was not completed. The number of patients analysed is small.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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