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    Clinical Trial Results:
    T-cell therapy in combination with vemurafenib for BRAF mutated metastatic melanoma

    Summary
    EudraCT number
    		 2014-001419-38
    Trial protocol
    		 DK  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2020
    First version publication date
    18 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MM1414
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02354690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Inge Marie Svane
    Sponsor organisation address
    Borgmester Ib Juuls Vej 25C, Herlev, Denmark, 2730
    Public contact
    Inge Marie Svane, National Center for Cancer Immune Therapy, 0045 38689339, inge.marie.svane@regionh.dk
    Scientific contact
    Inge Marie Svane, National Center for Cancer Immune Therapy, 0045 38689339, inge.marie.svane@regionh.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate toxicity (according to CTCAE version 4.0) and feaseability.
    Protection of trial subjects
    Patients were treated according to best practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    11
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were included in Denmark from November 2014 to April 2018.

    Pre-assignment
    Screening details
    		 Main inclusion criteria were metastatic melanoma with a tumor available for surgical resection and another measurable lesion according to RECIST. Performance status should be 0 or 1 without significant co-morbidities.

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

    Arms
    Arm title
    		 T cell therapy with vemurafenib pretreatment
    Arm description
    		 7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8). Lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission). TIL infusion: A tumor is surgically removed in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method. On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells). Interleukin-2 is administered according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tumor Infiltrating Lymphocytes
    Investigational medicinal product code
    Other name
    TIL
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    One-time intravenous infusion of 5x10e9 to 2x10e11 cultured autologous tumor infiltrating lymphocytes

    Number of subjects in period 1
    		T cell therapy with vemurafenib pretreatment
    Started
    13
    Received T cell infusion
    12
    Completed
    12
    Not completed
    1
         Disease progression
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 13 13
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 2 2
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 7 7
    M stage
    M stage according to the AJCC melanoma 7th edition classification
    Units: Subjects
        M1a
    		 1 1
        M1b
    		 1 1
        M1c
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    T cell therapy with vemurafenib pretreatment
    Reporting group description
    		 7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8). Lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission). TIL infusion: A tumor is surgically removed in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method. On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells). Interleukin-2 is administered according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours)

    Primary: Number of reported adverse events

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    End point title
    		 Number of reported adverse events [1]
    End point description
    From start of treatment until 24 weeks after T cell infusion
    End point type
    Primary
    End point timeframe
    0-40 weeks
    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: The assessment of the endpoint is descriptional and due to the single arm design no statistics are to be performed.
    End point values
    		 T cell therapy with vemurafenib pretreatment
    Number of subjects analysed
    12
    Units: adverse events
        Grade 1-2
    89
        Grade 3-4
    35
        Total
    124
    No statistical analyses for this end point

    Secondary: Treatment related immune responses

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    End point title
    		 Treatment related immune responses
    End point description
    Measurable anti-tumor reactive T cells in the infusion product
    End point type
    Secondary
    End point timeframe
    0-24 weeks
    End point values
    		 T cell therapy with vemurafenib pretreatment
    Number of subjects analysed
    12
    Units: Participants
        Infusion product contains reactive T cells
    10
        Reactive T cells not found in infusion product
    2
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Complete or partial response according to RECIST1.1.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    		 T cell therapy with vemurafenib pretreatment
    Number of subjects analysed
    12
    Units: Response
        Complete response
    1
        Partial response
    8
        Stable disease
    3
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
    End point type
    Secondary
    End point timeframe
    Up to 40 months
    End point values
    		 T cell therapy with vemurafenib pretreatment
    Number of subjects analysed
    12
    Units: Months
    median (full range (min-max))
        Median overall survival
    28.8 (5.2 to 39.9)
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival (PFS), defined as the time from start of treatment to disease progression, relapse or death due to any cause, whichever is earlier, will be described with the Kaplan-Meier curve.
    End point type
    Secondary
    End point timeframe
    Up to 40 months
    End point values
    		 T cell therapy with vemurafenib pretreatment
    Number of subjects analysed
    12
    Units: Months
    median (full range (min-max))
        Median progression-free survival
    4.8 (2.5 to 36.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment to 24 weeks after T cell infusion.
    Adverse event reporting additional description
    Adverse events were collected continually and as a minimum systematically at baseline, each treatment visit and at follow-up visits until 24 weeks after T cell infusion.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia without neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
    Additional description: Related to prior systemic anti-cancer treatment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Pancreatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    General disorders and administration site conditions
    Pyrexia
    Additional description: Pyrexia without neutropenia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    14
    Immune system disorders
    Rhinitis atrophic
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    10
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hallucination
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Neutropenia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    13
    Lymphopenia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    13
    Thrombocytopenia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    13
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Oral mucositis
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Hepatobiliary disorders
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    14
    Petechiae
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Vitiligo
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Papilloma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Actinic keratosis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Photosensitivity
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    10
    Infections and infestations
    Infection
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Apr 2017
    Prolongation of inclusion period due to slow accrual.
    31 Dec 2018
    Description of follow-up was changed to allow for early closure of the trial.

    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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