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    Clinical Trial Results:
    A Randomized Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Treatment with OncoVEX^GM-CSF Compared to Subcutaneously Administered GM-CSF in Melanoma Patients with Unresectable Stage IIIb, IIIc and IV Disease

    Summary
    EudraCT number
    		 2008-006140-20
    Trial protocol
    		 GB  
    Global end of trial date
    08 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2016
    First version publication date
    21 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    005/05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00769704
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 20110263: Amgen study ID
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the efficacy and safety of treatment with talimogene laherparepvec compared to subcutaneously administered GM-CSF in patients with unresectable Stage IIIb, IIIc and Stage IV melanoma. The efficacy endpoints of the study aim to demonstrate overall clinical benefit for patients treated with talimogene laherparepvec as compared to GM-CSF.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Written informed consent, properly witnessed and executed, was obtained from each subject before study entry. The protocol, informed consent, and other appropriate study documentation were approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) of each study center before the study began.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 383
    Worldwide total number of subjects
    437
    EEA total number of subjects
    33
    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)
    225
    From 65 to 84 years
    191
    85 years and over
    21

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were adults with histologically confirmed, not surgically resectable, stage IIIB - IV melanoma suitable for direct or ultrasound-guided injection. Among those randomized, the first patient enrolled 29 April 2009 and last patient enrolled 8 June 2011. 1 patient randomized 3 times is counted once under talimogene laherparepvec.

    Pre-assignment
    Screening details
    		 Patients were assigned at a 2:1 ratio using central random assignment to receive intralesional talimogene laherparepvec or subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF). Randomization was stratified by site of first recurrence, presence of liver metastases, disease stage, and prior nonadjuvant systemic treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GM-CSF
    Arm description
    		 Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    GM-CSF
    Investigational medicinal product code
    Other name
    Leukine, Sargramostim
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    125 µg/m² subcutaneous injection

    Arm title
    		 Talimogene Laherparepvec
    Arm description
    		 Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10^6 plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10^8 PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Talimogene laherparepvec
    Investigational medicinal product code
    Other name
    OncoVEX^GM-CSF, IMLYGIC™
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    Up to 4 mL of 10⁸ pfu/mL/per intratumoral injection

    Number of subjects in period 1
    		GM-CSF Talimogene Laherparepvec
    Started
    141
    296
    Intent-to-treat Population
    141
    295
    Received Treatment
    127
    292
    Completed
    30
    97
    Not completed
    111
    199
         Consent withdrawn by subject
    12
    5
         Death
    95
    190
         Other
    1
    2
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GM-CSF
    Reporting group description
    		 Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.

    Reporting group title
    Talimogene Laherparepvec
    Reporting group description
    		 Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10^6 plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10^8 PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.

    Reporting group values
    		 GM-CSF Talimogene Laherparepvec Total
    Number of subjects
    		 141 296 437
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 72 153 225
        From 65-84 years
    		 63 128 191
        85 years and over
    		 6 15 21
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.92 ( 14.13 ) 63.07 ( 13.68 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 64 123 187
        Male
    		 77 173 250
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 138 290 428
        Black
    		 2 1 3
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Other
    		 1 3 4
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Scale used to assess how a patient's disease is progressing, how the disease affects the daily living abilities of the patient: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to a bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0
    		 97 210 307
        Grade 1
    		 32 82 114
        Missing
    		 12 4 16
    Tumor, Node, Metastasis (TNM) Disease Stage
    Stage IIIB: Ulcerated lesion and 1 lymph node or 2-3 nodes with micrometastasis, or any-depth lesion with no ulceration, and 1 lymph node or 2-3 nodes with macrometastasis; Stage IIIC: Ulcerated lesion and 1 lymph node with macrometastasis; 2-3 nodes with macrometastasis or ≥4 metastatic lymph nodes, matted lymph nodes, or in-transit met(s)/satellite(s); Stage IV: M1a: Spread to skin, subcutaneous tissue, or lymph nodes; normal lactate dehydrogenase (LDH) level; M1b: Spread to lungs, normal LDH; M1c: Spread to all other visceral organs, normal LDH or any distant disease with elevated LDH.
    Units: Subjects
        Stage IIIB
    		 12 22 34
        Stage IIIC
    		 31 66 97
        Stage IV M1a
    		 43 76 119
        Stage IV M1b
    		 26 64 90
        Stage IV M1c
    		 29 67 96
        Missing
    		 0 1 1
    Line of Therapy
    Units: Subjects
        First Line
    		 65 138 203
        Second Line or Greater
    		 76 158 234

    End points

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    End points reporting groups
    Reporting group title
    GM-CSF
    Reporting group description
    		 Granulocyte macrophage colony-stimulating factor (GM-CSF) was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.

    Reporting group title
    Talimogene Laherparepvec
    Reporting group description
    		 Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose of talimogene laherparepvec was at a concentration of 10^6 plaque forming units (PFU)/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10^8 PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.

    Primary: Durable Response Rate

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    End point title
    		 Durable Response Rate
    End point description
    Durable response rate was defined as the percentage of participants with a complete response (CR) or partial response (PR) maintained continuously for at least 6 months from the time the objective response was first observed and initiating within 12 months of starting therapy as assessed by the Endpoint Assessment Committee (EAC). This reflects all new sites of disease as well as disease sites identified at baseline. Disease assessments were performed at the beginning of each treatment cycle in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline. The intent-to-treat population included all participants randomized to receive study treatment, excluding one participant who was randomized three times.
    End point type
    Primary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    141
    295
    Units: percentage of participants
        number (confidence interval 95%)
    2.1 (0 to 4.5)
    16.3 (12.1 to 20.5)
    Statistical analysis title
    		 Treatment Difference
    Statistical analysis description
    The null hypothesis was that there was no difference in the durable response rate between the talimogene laherparepvec and control arms. Study success was defined as the rejection of this hypothesis such that talimogene laherparepvec was found to be superior to GM-CSF using the 2-sided Fisher’s exact test, with a p-value of ≤ 0.0488.
    Comparison groups
    Talimogene Laherparepvec v GM-CSF
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Treatment Difference
    Point estimate
    14.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.3
         upper limit
    		 19

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from the date of randomization to the date of death from any cause. Overall survival time was censored at the last date the patient was known to be alive when the confirmation of death was absent or unknown. Participants were censored at the date of randomization if no additional follow-up data were obtained.
    End point type
    Secondary
    End point timeframe
    From randomization until the first 290 survival events had occurred (data cut-off date of 31 March 2014); median time on follow-up was 44 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    141
    295
    Units: months
        median (confidence interval 95%)
    18.9 (16 to 23.7)
    23.3 (19.5 to 29.6)
    Statistical analysis title
    		 Overall Survival Analysis
    Statistical analysis description
    The primary method for analysis of overall survival was an unadjusted log-rank test. Testing of overall survival was conditional on a statistically significance difference in the primary endpoint of durable response. Success was defined as a p-value ≤ 0.05. The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average death rate and a longer overall survival for talimogene laherparepvec relative to GM-CSF.
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0511
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response rate was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed by the Endpoint Assessment Committee (EAC). Best overall response for a patient is the best overall response observed across all time points. Disease assessments were performed at the beginning of each treatment cycle and assessed in accordance with modified World Health Organization criteria. CR: Disappearance of all clinical evidence of tumor (both measurable and non-measurable but evaluable disease); PR: ≥ 50% reduction in the sum of the products of the perpendicular diameters of all measurable tumors at the time of assessment as compared to baseline.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    141
    295
    Units: percentage of participants
        number (confidence interval 95%)
    5.7 (1.9 to 9.5)
    26.4 (21.4 to 31.5)
    Statistical analysis title
    		 Objective Response Rate Treatment Difference
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Fisher exact
    Parameter type
    		 Treatment Difference
    Point estimate
    20.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.4
         upper limit
    		 27.1
    Notes
    [1] - Descriptive

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    The duration of response is defined as the longest individual period from entering response (CR or PR as assessed by the EAC) to the first documented evidence of the patient no longer meeting the criteria for being in response or death, whichever is earlier. Responses were censored at the last assessment showing response. "99999" indicates data that could not be estimated due to the low number of events
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    8 [2]
    78 [3]
    Units: months
        median (confidence interval 95%)
    2.8 (1.2 to 99999)
    99999 (99999 to 99999)
    Notes
    [2] - Participants with an objective response (CR or PR) per EAC assessment.
    [3] - Participants with an objective response (CR or PR) per EAC assessment.
    Statistical analysis title
    		 Duration of Response Analysis
    Statistical analysis description
    The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer average duration of response for talimogene laherparepvec relative to GM-CSF.
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0868 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.18
    Notes
    [4] - Descriptive

    Secondary: Response Onset

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    End point title
    		 Response Onset
    End point description
    Response onset is defined as the time from the date of randomization to the date of the first documented evidence of response (CR or PR) per EAC assessment.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    8 [5]
    78 [6]
    Units: months
        median (confidence interval 95%)
    3.7 (1.9 to 5.6)
    4.1 (3.8 to 5.4)
    Notes
    [5] - Participants with an objective response (CR or PR) per EAC assessment.
    [6] - Participants with an objective response (CR or PR) per EAC assessment.
    Statistical analysis title
    		 Response Onset Analysis
    Statistical analysis description
    The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio > 1.0 indicates a a higher average response onset rate for talimogene laherparepvec relative to GM-CSF.
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.202 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.3
    Notes
    [7] - Descriptive

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    Time to treatment failure was assessed by the investigator, and calculated from randomization until the first clinically relevant disease progression where there is no response achieved after the progression, or until death if no such progression occurs. Participants who did not have clinically relevant progression or did not die were censored at the time of the their last tumor assessment. Participants who withdrew from treatment due to a clinically unacceptable toxicity were not considered as an event in the analysis. Progressive disease (PD) is defined as a ≥ 25% increase in the sum of the products of the perpendicular diameters of all measurable tumors since baseline, or the unequivocal appearance of a new tumor since the last response assessment time point. Clinically relevant progressive disease is PD that is associated with a decline in performance status and/or in the opinion of the investigator the patient requires alternative therapy.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    141
    295
    Units: months
        median (confidence interval 95%)
    2.9 (2.8 to 4)
    8.2 (6.5 to 9.9)
    Statistical analysis title
    		 Time to Treatment Failure Analysis
    Statistical analysis description
    The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer average time to treatment failure for talimogene laherparepvec relative to GM-CSF.
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.54
    Notes
    [8] - Descriptive

    Secondary: Response Interval

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    End point title
    		 Response Interval
    End point description
    Response interval is defined as the interval between the date of randomization and the date of the last documented evidence of response (CR or PR as assessed by the Investigator) prior to any new anti-cancer therapy. Response Interval post response onset was censored if a patient was still in response at the last observation. "99999" indicates data that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 21 December 2012; median follow-up time was 20 months.
    End point values
    		 GM-CSF Talimogene Laherparepvec
    Number of subjects analysed
    9 [9]
    91 [10]
    Units: months
        median (confidence interval 95%)
    7.5 (1.9 to 99999)
    99999 (99999 to 99999)
    Notes
    [9] - Participants with an objective response (CR or PR) per Investigator assessment.
    [10] - Participants with an objective response (CR or PR) per Investigator assessment.
    Statistical analysis title
    		 Response Interval Analysis
    Statistical analysis description
    The hazard ratio was obtained from the unadjusted Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a longer response interval for talimogene laherparepvec relative to GM-CSF.
    Comparison groups
    GM-CSF v Talimogene Laherparepvec
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.73
    Notes
    [11] - Descriptive

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until 30 days after the last dose until the data cut off date of 8 August 2014; median treatment duration was 10.0 weeks (0.6 to 120.0 weeks) in the GM-CSF arm and 23.1 weeks (0.1 to 176.7 weeks) in the talimogene laherparepvec arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Talimogene Laherparepvec
    Reporting group description
    		 Participants received talimogene laherparepvec on Days 1 and 15 of each 28-day cycle for 24 weeks. The initial dose was at a concentration of 10^6 PFU/mL, injected into 1 or more skin, subcutaneous or nodal tumors. Subsequent doses began at least 3 weeks after the first dose and consisted of talimogene laherparepvec at a concentration of 10^8 PFU/mL. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or disappearance of all injectable lesions, for a maximum of 18 months.

    Reporting group title
    GM-CSF
    Reporting group description
    		 GM-CSF was administered at a dose of 125 μg/m²/day subcutaneously for 14 days in 28-day cycles for 24 weeks. Participants could continue treatment until clinically relevant disease progression, intolerability, withdrawal of consent, complete remission, or lack of response by 12 months, for a maximum of 18 months.

    Serious adverse events
    		 Talimogene Laherparepvec GM-CSF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 292 (27.40%)
    17 / 127 (13.39%)
         number of deaths (all causes)
    12
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma of liver
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    3 / 292 (1.03%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma recurrent
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    3 / 292 (1.03%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    4 / 292 (1.37%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    4 / 292 (1.37%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 292 (1.03%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    10 / 292 (3.42%)
    2 / 127 (1.57%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 292 (1.71%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Obstructive airways disorder
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 292 (1.37%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation associated pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound decomposition
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    3 / 292 (1.03%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocephalus
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 292 (1.03%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pain of skin
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 292 (0.68%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal papillary necrosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 292 (0.34%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    7 / 292 (2.40%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 292 (0.68%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 292 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 292 (0.34%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Talimogene Laherparepvec GM-CSF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    282 / 292 (96.58%)
    113 / 127 (88.98%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    20 / 292 (6.85%)
    7 / 127 (5.51%)
         occurrences all number
    29
    7
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    143 / 292 (48.97%)
    11 / 127 (8.66%)
         occurrences all number
    377
    28
    Fatigue
         subjects affected / exposed
    148 / 292 (50.68%)
    46 / 127 (36.22%)
         occurrences all number
    343
    69
    Influenza like illness
         subjects affected / exposed
    89 / 292 (30.48%)
    19 / 127 (14.96%)
         occurrences all number
    335
    37
    Injection site erythema
         subjects affected / exposed
    15 / 292 (5.14%)
    33 / 127 (25.98%)
         occurrences all number
    15
    51
    Injection site reaction
         subjects affected / exposed
    9 / 292 (3.08%)
    12 / 127 (9.45%)
         occurrences all number
    13
    19
    Injection site pruritus
         subjects affected / exposed
    5 / 292 (1.71%)
    21 / 127 (16.54%)
         occurrences all number
    7
    26
    Injection site pain
         subjects affected / exposed
    83 / 292 (28.42%)
    8 / 127 (6.30%)
         occurrences all number
    146
    11
    Injection site swelling
         subjects affected / exposed
    11 / 292 (3.77%)
    8 / 127 (6.30%)
         occurrences all number
    14
    12
    Oedema peripheral
         subjects affected / exposed
    38 / 292 (13.01%)
    12 / 127 (9.45%)
         occurrences all number
    50
    20
    Pain
         subjects affected / exposed
    48 / 292 (16.44%)
    13 / 127 (10.24%)
         occurrences all number
    67
    19
    Pyrexia
         subjects affected / exposed
    122 / 292 (41.78%)
    11 / 127 (8.66%)
         occurrences all number
    301
    24
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    18 / 292 (6.16%)
    2 / 127 (1.57%)
         occurrences all number
    24
    4
    Dyspnoea
         subjects affected / exposed
    14 / 292 (4.79%)
    14 / 127 (11.02%)
         occurrences all number
    16
    19
    Cough
         subjects affected / exposed
    31 / 292 (10.62%)
    11 / 127 (8.66%)
         occurrences all number
    43
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 292 (6.51%)
    2 / 127 (1.57%)
         occurrences all number
    21
    2
    Depression
         subjects affected / exposed
    16 / 292 (5.48%)
    3 / 127 (2.36%)
         occurrences all number
    16
    3
    Insomnia
         subjects affected / exposed
    21 / 292 (7.19%)
    6 / 127 (4.72%)
         occurrences all number
    22
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    17 / 292 (5.82%)
    1 / 127 (0.79%)
         occurrences all number
    22
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    15 / 292 (5.14%)
    3 / 127 (2.36%)
         occurrences all number
    16
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 292 (10.62%)
    4 / 127 (3.15%)
         occurrences all number
    34
    4
    Headache
         subjects affected / exposed
    55 / 292 (18.84%)
    12 / 127 (9.45%)
         occurrences all number
    104
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 292 (5.14%)
    2 / 127 (1.57%)
         occurrences all number
    22
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 292 (9.25%)
    3 / 127 (2.36%)
         occurrences all number
    48
    3
    Constipation
         subjects affected / exposed
    34 / 292 (11.64%)
    8 / 127 (6.30%)
         occurrences all number
    63
    8
    Diarrhoea
         subjects affected / exposed
    57 / 292 (19.52%)
    14 / 127 (11.02%)
         occurrences all number
    82
    24
    Dyspepsia
         subjects affected / exposed
    15 / 292 (5.14%)
    8 / 127 (6.30%)
         occurrences all number
    16
    10
    Nausea
         subjects affected / exposed
    106 / 292 (36.30%)
    25 / 127 (19.69%)
         occurrences all number
    191
    28
    Vomiting
         subjects affected / exposed
    63 / 292 (21.58%)
    12 / 127 (9.45%)
         occurrences all number
    96
    15
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    22 / 292 (7.53%)
    9 / 127 (7.09%)
         occurrences all number
    29
    11
    Hyperhidrosis
         subjects affected / exposed
    23 / 292 (7.88%)
    9 / 127 (7.09%)
         occurrences all number
    34
    15
    Night sweats
         subjects affected / exposed
    6 / 292 (2.05%)
    7 / 127 (5.51%)
         occurrences all number
    6
    13
    Pruritus
         subjects affected / exposed
    29 / 292 (9.93%)
    19 / 127 (14.96%)
         occurrences all number
    37
    33
    Rash
         subjects affected / exposed
    27 / 292 (9.25%)
    10 / 127 (7.87%)
         occurrences all number
    32
    11
    Vitiligo
         subjects affected / exposed
    18 / 292 (6.16%)
    1 / 127 (0.79%)
         occurrences all number
    18
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    15 / 292 (5.14%)
    5 / 127 (3.94%)
         occurrences all number
    16
    5
    Muscle spasms
         subjects affected / exposed
    13 / 292 (4.45%)
    7 / 127 (5.51%)
         occurrences all number
    14
    10
    Back pain
         subjects affected / exposed
    30 / 292 (10.27%)
    8 / 127 (6.30%)
         occurrences all number
    46
    9
    Arthralgia
         subjects affected / exposed
    51 / 292 (17.47%)
    11 / 127 (8.66%)
         occurrences all number
    71
    14
    Musculoskeletal pain
         subjects affected / exposed
    14 / 292 (4.79%)
    7 / 127 (5.51%)
         occurrences all number
    20
    7
    Myalgia
         subjects affected / exposed
    52 / 292 (17.81%)
    7 / 127 (5.51%)
         occurrences all number
    119
    7
    Neck pain
         subjects affected / exposed
    15 / 292 (5.14%)
    7 / 127 (5.51%)
         occurrences all number
    18
    8
    Pain in extremity
         subjects affected / exposed
    48 / 292 (16.44%)
    12 / 127 (9.45%)
         occurrences all number
    65
    12
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 292 (5.14%)
    2 / 127 (1.57%)
         occurrences all number
    22
    2
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 292 (10.27%)
    8 / 127 (6.30%)
         occurrences all number
    36
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 292 (10.27%)
    14 / 127 (11.02%)
         occurrences all number
    34
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2009
    - Subjects with previously untreated melanoma were allowed to enroll. - Permitted medications were updated to allow for oral and systemic steroid use. - Baseline brain MRI was included as a measure to assess disease status. - The use of liquid GM-CSF was added.
    08 Jul 2010
    - Survival follow-up was increased from 2 years to 3 years from the time of randomization. - Subjects were allowed to continue to receive study treatment during corticosteroid therapy following stereotactic radiotherapy providing that the total daily dose did not exceed the equivalent of 10 mg prednisone. - Exclusion criteria were updated to allow subjects with a second cancer to enroll if they were diagnosed at a stage where definitive therapy results in near certain cure (with Medical Monitor approval). - Subjects with a total cumulative tumor burden in excess of 20 cm were allowed to enroll with Medical Monitor approval. - Injectable local anesthetic was allowed during talimogene laherparepvec administration, and procedures required during the 4-hour period after the first injection were clarified. - GM-CSF dosing modifications were clarified. - A photographic requirement for events of vitiligo was added.

    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.
    None reported
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