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    Clinical Trial Results:
    A Phase 1, Multi center, Open label, Dose De escalation Study to Evaluate the Safety and Efficacy of Talimogene Laherparepvec in Pediatric Subjects with Advanced Non central Nervous System Tumors That are Amenable to Direct Injection

    Summary
    EudraCT number
    		 2015-003645-25
    Trial protocol
    		 ES   FR   SE   BE   IT  
    Global end of trial date
    29 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jun 2023
    First version publication date
    11 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110261
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02756845
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Scientific contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001251-PIP01-11
    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
    29 Nov 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to determine the safety and tolerability of talimogene laherparepvec, as assessed by incidence of dose limiting toxicities (DLT), in pediatric participants with advanced non central nervous system (CNS) tumors that are amenable to direct injection.
    Protection of trial subjects
    This trial was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Aug 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    15
    EEA total number of subjects
    10
    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)
    2
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 15 participants were enrolled across 11 centers in Belgium, Canada, France, Spain, Switzerland and the United States from August 2017 to November 2022.

    Pre-assignment
    Screening details
    		 Participants were screened to determine if they were eligible to join the trial up to 28 days prior to receiving their first dose. All participants received talimogene laherparepvec.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years
    Arm description
    		 Participants aged 12 to ≤ 21 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    Other name
    TVEC
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Participants were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months.

    Arm title
    		 Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Arm description
    		 Participants aged 2 to < 12 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    Other name
    TVEC
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralesional use
    Dosage and administration details
    Participants were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months.

    Number of subjects in period 1
    		Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Started
    13
    2
    Received Talimogene Laherparepvec
    13
    2
    Completed
    0
    0
    Not completed
    13
    2
         Adverse event, serious fatal
    12
    2
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years
    Reporting group description
    		 Participants aged 12 to ≤ 21 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Reporting group title
    Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Reporting group description
    		 Participants aged 2 to < 12 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Reporting group values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years Total
    Number of subjects
    		 13 2 15
    Age categorical
    Units: Subjects
        2 - < 12 years
    		 0 2 2
        12 - 21 years
    		 13 0 13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.2 ( 2.8 ) 9.0 ( 2.8 ) -
    Sex: Female, Male
    Units:
        Female
    		 5 0 5
        Male
    		 8 2 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 10 1 11
        Unknown or Not Reported
    		 1 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 9 2 11
        Other
    		 3 0 3
        American Indian or Alaska Native
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years
    Reporting group description
    		 Participants aged 12 to ≤ 21 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Reporting group title
    Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Reporting group description
    		 Participants aged 2 to < 12 years were administered an initial dose of talimogene laherparepvec at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Primary: Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT)

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    End point title
    		 Percentage of Participants Who Experienced a Dose-limiting Toxicity (DLT) [1]
    End point description
    All toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0. The occurrence of any of the below was considered a DLT, if judged to be related to talimogene laherparepvec: •Grade 4 non-hematologic toxicity •Grade 3 non-hematologic toxicity that lasted > 3 days despite optimal supportive care •Any ≥ grade 3 non-hematologic laboratory value if medical intervention was required, the abnormality led to hospitalization or the abnormality persisted for > 1 week unless deemed not clinically important per both investigator & sponsor •Febrile neutropenia grade 3/4 •Thrombocytopenia < 25 x 10^9/L associated with bleeding event that required intervention •Serious herpetic event •Grade 5 toxicity •Any intolerable toxicity that led to permanent discontinuation of talimogene laherparepvec
    End point type
    Primary
    End point timeframe
    Day 1 to Day 35
    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: NA
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    11
    2
    Units: Percent of participants
    number (confidence interval 95%)
        Experienced a DLT
    0.0 (0.0 to 28.5)
    0.0 (0.0 to 84.2)
        Did Not Experience a DLT
    100.0 (71.5 to 100.0)
    100.0 (15.8 to 100.0)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from the date of an initial response of CR or PR to the earlier of PD/death. 99999 - no evaluable data. No participants experienced a response of CR or PR, so DOR could not be calculated.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Days
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants who experienced either complete response (CR) or partial response (PR) per modified immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) response criteria. CR was defined as the disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks (28 days) from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as the decrease in tumor burdena ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks (28 days) after first documentation.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (0.00 to 24.71)
    0.0 (0.00 to 84.19)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    TTR was defined as the number of days from the first dose of talimogene laherparepvec to the first objective assessment of response as per modified irRC-RECIST. 99999 - no evaluable data. No participants experienced a response of CR or PR, so TTR could not be calculated.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Days
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    TTP was defined as the time from the first dose of talimogene laherparepvec until objective tumor progression per irRC-RECIST. TTP was estimated using the Kaplan-Meier method. 1.99999 - no evaluable data. Insufficient number of participants experienced disease progression, so TTP could not be calculated.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Months
        median (full range (min-max))
    2.50 (0.0 to 9.0)
    1.99999 (1.6 to 3.5)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the first dose to the earlier of disease progression per modified irRC-RECIST or death from any cause. PFS was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Months
        median (full range (min-max))
    3.32 (1.1 to 11.6)
    6.42 (1.6 to 11.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as as the time from first dose to the event of death from any cause. OS was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks until the end of follow-up; maximum duration of follow-up was 54.51 months
    End point values
    		 Cohort A1: Talimogene Laherparepvec - Aged 12 to ≤ 21 Years Cohort B1: Talimogene Laherparepvec - Aged 2 to < 12 Years
    Number of subjects analysed
    13
    2
    Units: Months
        median (full range (min-max))
    9.40 (1.1 to 54.5)
    8.02 (4.8 to 11.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: Day 1 to end of follow-up, maximum duration of follow-up = 54.51 months. AEs: Day 1 to 30 days after last dose. Maximum duration of treatment = 9.1 months in T-VEC Cohort A1 and 3.6 months in T-VEC Cohort B1
    Adverse event reporting additional description
    Adverse events and serious adverse event are reported for all participants who received at least one dose of talimogene laherparepvec. Duration of treatment = ((The date of last dose of study drug - The date of first dose of study drug + 1)/365.25 * 12).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    T-VEC Cohort B1: Aged 2 to < 12 Years
    Reporting group description
    		 Participants aged 2 to < 12 years were administered an initial dose of talimogene laherparepvec (T-VEC) at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Reporting group title
    T-VEC Cohort A1: Aged 12 to ≤ 21 Years
    Reporting group description
    		 Participants aged 12 to ≤ 21 years were administered an initial dose of talimogene laherparepvec (T-VEC) at a dose of up to 4.0 mL of 10ᶺ6 PFU/mL followed by a dose of up to 4.0 mL of 10ᶺ8 PFU/mL 21 days (± 3) later. All subsequent injections, up to 4.0 mL of 10^8 PFU/mL were administered every 14 (± 3) days for up to approximately 9 months. Talimogene laherparepvec was administered by intralesional injection only into injectable cutaneous, subcutaneous, nodal tumors, and other non-visceral tumors with or without image ultrasound guidance.

    Serious adverse events
    		 T-VEC Cohort B1: Aged 2 to < 12 Years T-VEC Cohort A1: Aged 12 to ≤ 21 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    5 / 13 (38.46%)
         number of deaths (all causes)
    2
    12
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Osteosarcoma metastatic
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cranial nerve disorder
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Vascular device infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 T-VEC Cohort B1: Aged 2 to < 12 Years T-VEC Cohort A1: Aged 12 to ≤ 21 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    13 / 13 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Haemorrhage
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Embolism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    9
    Face oedema
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    22
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    Chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 2 (100.00%)
    9 / 13 (69.23%)
         occurrences all number
    5
    22
    Malaise
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Injection site pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    Injection site inflammation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    5
    Oedema peripheral
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    Disease progression
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    General physical condition abnormal
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Heat cramps
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Wound dehiscence
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Wound complication
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    Sinus tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 2 (50.00%)
    5 / 13 (38.46%)
         occurrences all number
    1
    13
    Neuralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    4
    Coagulopathy
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    Dry mouth
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Vomiting
         subjects affected / exposed
    1 / 2 (50.00%)
    6 / 13 (46.15%)
         occurrences all number
    1
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Endocrine disorders
    Autoimmune hypothyroidism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    Muscle spasms
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Joint contracture
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Arthralgia
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    11
    Musculoskeletal pain
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 2 (50.00%)
    4 / 13 (30.77%)
         occurrences all number
    2
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    Mastitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nail infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 13 (7.69%)
         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
    04 Apr 2017
    * The upper age limit of eligible participants has been changed from 18 to 21 years of age * The lowest age cohort (0 to < 2 years of age) has been removed because of the following reasons: − the perceived toxicity risk of treating these pediatric patients, who have an immature immune system, with talimogene laherparepvec − the anticipated low benefit of talimogene laherparepvec treatment for this population for which standard of care and other proven salvage regimens are available for the type of advanced/recurrent/refractory pediatric tumor(s) seen in this age subset * The requirement to enroll participants according to herpes simplex virus type 1 (HSV-1) serostatus has been removed because of the following reasons: − low prevalence of HSV-1 positivity in the pediatric population − the addition of a recommendation to use premedication to mitigate the side effects of talimogene laherparepvec in HSV-1 negative participants * Maximum number of participants enrolled was changed from 36 to 27 subjects because of the changes in the age cohorts.
    04 Apr 2017
    Amendment continued: * Background and Rationale was updated with background information that supports changes to the study design. * Eligibility criteria were clarified and updated to reflect changes in the study design. * Recommendation to use premedication with the appropriate antipyretic and/or antiemetic medications prior to each talimogene laherparepvec treatment was added to Dosage, Administration, and Schedule Rules for DLT evaluation were clarified and stopping rules were updated. * Rules for opening younger age cohort were updated. * Rules for dose de-escalation were updated. * Childhood vaccinations that contain live attenuated virus were added to the list of excluded treatments. * Schedule of Assessments table was updated to: − clarify the timing of procedures. − add an additional pregnancy test and performance status assessments * Laboratory Assessments was updated to clarify which tests will be done locally versus centrally. * Text describing reporting procedures for serious adverse events was moved from Reporting Serious Adverse Events After the Protocol-required Reporting Period to Reporting Procedures for Serious Adverse Events. * Exploratory endpoints were updated. * Statistical Considerations was updated to reflect changes in the study design. * Appendix D was updated to clarify assessments for tumor response.
    10 Oct 2018
    * Update end of study language to align with the current protocol template language * Update contraception language to align with the current risk and discomforts language * Clarify transfusion timeframe in Inclusion Criterion 115 to ensure that adequate hematologic function is not confounded by a recent transfusion or growth factor support * Clarify that participants with history or evidence of giant congenital melanocytic nevi or dysplastic nevis syndrome are not excluded from the study because such participants are at risk of developing advanced melanoma with injectable disease and will therefore be eligible for the study * Shorten the washout period for prior chemotherapy, treatment dose radiotherapy, or biological cancer therapy from 28 days to 14 days prior to enrollment * Clarify that coagulation tests are only required at screening * Update the number of sites participating in the study * Update disease-related events language * Remove ‘Reporting a Safety Endpoint as a Study Endpoint’ section as this section is not applicable to this study * Update the matrix for determining the overall response to account for when nontarget lesion assessment was not done * Remove self-evident corrections language
    12 Jun 2020
    Updated: * the number of pediatric participants to be enrolled for the study from 18 to 27 to 18 to 24; * the number of DLT evaluable participants from 9 to 6 in the event of a dose de-escalation * the maximum of 18 participants treated with at least 1 dose of talimogene laherparepvec with at least 9 DLT-evaluable participants in cohort A1. Update sample size considerations and DLT evaluation: * From 6 to 12 DLT-evaluable participants to 18 to 24 participants enrolled and treated with at least 1 dose of talimogene laherparepvec with at least 9 DLT-evaluable participants in cohort A1 * Clarify the 3+3 phase 1 design is for age cohort opening and dose de-escalation, assuming a true DLT incidence rate < 33% is used (with a minimum of 6 DLT-evaluable participants ) * Sample size for cohorts with age between 2 and 12 years are not required. * Clarified that after both cohorts are open, the Dose Level Review Team (DLRT) can review the safety data after the addition of 3 new DLT-evaluable participants in a cohort until there’re 9 DLT-evaluable participants in the cohort. Additionally, ad-hoc meetings to review the safety data can be convened anytime, if deemed necessary. These changes were made to maximize the efficiency of the DLRT meeting based on safety need. * Updated the definition for primary completion date to occur 35 days after the last participant has enrolled and received at least 1 dose of talimogene laherparepvec. The definition is modified based on the changes in the minimum number of DLT evaluable participants for each cohort. * Updated objectives/endpoints * Added exploratory objectives and endpoint Inclusion criteria definition for adequate organ function is updated for * hematological: no transfusion/growth factor support within 7 days from screening assessment instead of 4 weeks from screening blood count * hepatic: serum bilirubin ≤ 1.5× baseline value if baseline value was abnormal for a participant with Gilbert’s syndrome.
    12 Jun 2020
    Amendment continued: Exclusion criteria updated: * for central nervous system (CNS) tumor or clinically active brain metastases updated with the clarification that participants with a history of treated brain metastases shall be eligible if they fulfill the following criteria: radiographic evidence of improvement with CNS-directed therapy, and no interim progression is observed * for receiving treatment in another investigational study device or study drug and major surgery updated to 14 days since ending treatment * Major surgery ≤ 14 days prior to enrollment or has not recovered to CTCAE version 4.0 grade 1 or better from adverse event due to surgery performed more than 14 days prior to enrollment * Updated language for reporting the serious disease-related events as all events to be reported to sponsor or designee within 24 hours

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Participant recruitment ended when 15 participants were enrolled due to difficulties in enrollment.
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