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    Clinical Trial Results:
    T cell therapy in combination with peginterferon for metastatic malignant melanoma

    Summary
    EudraCT number
    		 2014-001420-29
    Trial protocol
    		 DK  
    Global end of trial date
    17 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2018
    First version publication date
    14 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MM1413
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02379195
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Center for Cancer Immune Therapy, Herlev Hospital
    Sponsor organisation address
    Herlev Ringvej 75, Herlev, Denmark, 2730
    Public contact
    Center for Cancer Immune Therapy, Center for Cancer Immune Therapy, +45 38683868, inge.marie.svane@regionh.dk
    Scientific contact
    Center for Cancer Immune Therapy, Center for Cancer Immune Therapy, +45 38683868, 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
    17 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 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 feasibility
    Protection of trial subjects
    Palliative medications as needed
    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: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    16
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were screened in Denmark between November 2014 and May 2017.

    Pre-assignment
    Screening details
    		 Patients were screened in a two-stage model. For inclusion for surgery patients were screened with blood samples, PET/CT scan of the body and MRI of the brain. A total of 23 patients were included for surgery. 12 patients were enrolled for treatment with T-cell therapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TIL + IFNa
    Arm description
    		 The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on day -7 to day -1. The TILs are infused on day 0 and Interleukin-2 therapy are administered on day 0 to day 5. Interleukin-2 are administered in an i.v. continuous decrescendo regimen starting approximately 6 hours after TIL infusion with a duration of approximately 5 days Subcutaneous injections of peginterferon alpha 2b are administered three time (day -2, day 7 and day 14)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tumor-infiltrating lymphocytes
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Maximum number of expanded TILs (20-200 x 10^9) are infused intravenously once

    Arm title
    		 Surgery
    Arm description
    		 Patients enrolled for surgery, but did not receive treatment.
    Arm type
    		 Surgery

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		TIL + IFNa Surgery
    Started
    12
    11
    Completed
    12
    0
    Not completed
    0
    11
         Consent withdrawn by subject
    -
    1
         Progression/clinical deterioration
    -
    4
         Did not progress after surgery
    -
    5
         Removed tumor was not melanoma
    -
    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
    		 23 23
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Adults (18-70)
    		 23 23
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 13 13

    End points

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    End points reporting groups
    Reporting group title
    TIL + IFNa
    Reporting group description
    		 The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on day -7 to day -1. The TILs are infused on day 0 and Interleukin-2 therapy are administered on day 0 to day 5. Interleukin-2 are administered in an i.v. continuous decrescendo regimen starting approximately 6 hours after TIL infusion with a duration of approximately 5 days Subcutaneous injections of peginterferon alpha 2b are administered three time (day -2, day 7 and day 14)

    Reporting group title
    Surgery
    Reporting group description
    		 Patients enrolled for surgery, but did not receive treatment.

    Primary: Tolerability and feasibility

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    End point title
    		 Tolerability and feasibility [1]
    End point description
    End point type
    Primary
    End point timeframe
    3 years
    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 primary endpoint is tolerability and feasibility. The treatment was both tolerable and feasible. Statistical analysis on this endpoint is not feasible.
    End point values
    		 TIL + IFNa Surgery
    Number of subjects analysed
    12
    11
    Units: Tolerable
        number (not applicable)
    12
    11
    No statistical analyses for this end point

    Secondary: Median overall survival

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    End point title
    		 Median overall survival [2]
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Median overall survival is only provided for the treatment arm.
    End point values
    		 TIL + IFNa
    Number of subjects analysed
    12
    Units: months
        median (full range (min-max))
    11.75 (0.13 to 27.33)
    No statistical analyses for this end point

    Secondary: Median progression-free survival

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    End point title
    		 Median progression-free survival [3]
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Median overall survival is only provided for the treatment arm.
    End point values
    		 TIL + IFNa
    Number of subjects analysed
    12
    Units: months
        median (full range (min-max))
    2.8 (0.13 to 18.4)
    No statistical analyses for this end point

    Secondary: Immune response

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    End point title
    		 Immune response [4]
    End point description
    Anti-tumor reactive T-cells in the infusion product
    End point type
    Secondary
    End point timeframe
    4 years
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Median overall survival is only provided for the treatment arm.
    End point values
    		 TIL + IFNa
    Number of subjects analysed
    12
    Units: Cell
        number (not applicable)
    4
    No statistical analyses for this end point

    Secondary: Overall response rate

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    End point title
    		 Overall response rate [5]
    End point description
    End point type
    Secondary
    End point timeframe
    3 years
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Median overall survival is only provided for the treatment arm.
    End point values
    		 TIL + IFNa
    Number of subjects analysed
    11
    Units: Percent
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    November 2014 - August 2018
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    TIL + IFNa
    Reporting group description
    		 The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) on day -7 to day -1. The TILs are infused on day 0 and Interleukin-2 therapy are administered on day 0 to day 5. Interleukin-2 are administered in an i.v. continuous decrescendo regimen starting approximately 6 hours after TIL infusion with a duration of approximately 5 days Subcutaneous injections of peginterferon alpha 2b are administered three time (day -2, day 7 and day 14)

    Serious adverse events
    		 TIL + IFNa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Nervous system disorders
    Vertigo
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Platelet count decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone marrow toxicity
    Additional description: After treatment patient's bone marrow recovered, but subsequently the patient developed low platelet counts, low leukocyte counts and anemia. No abnormalities were found on bone marrow biopsy and counts normalized spontaneously.
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Candida infection
    Additional description: Patient had oral- and oesophegal candidiasis leading to short-term hospitalization.
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Pneumonitis
         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: 1%
    Non-serious adverse events
    		 TIL + IFNa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Investigations
    Hypophosphataemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Confusion
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    General disorders and administration site conditions
    Fatique
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Alopecia
         subjects affected / exposed [1]
    11 / 11 (100.00%)
         occurrences all number
    11
    Ear and labyrinth disorders
    Hearing impairment
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Eye disorders
    Anterior uveitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Diarrhea
         subjects affected / exposed
    11 / 12 (91.67%)
         occurrences all number
    11
    Constipation
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Mucositis management
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Pulmonary oedema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Petechiae
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Myalgia
    Additional description: Myalgia/arthralgia
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Infections and infestations
    Infection
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Twelve patients were exposed to chemotherapy, but one patient died few days after and alopecia was not yet recorded for this patient.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2014
    Amended to not having to wait 6 weeks between treating study subjects.
    14 Dec 2015
    Amended to change principal investigator.
    15 Mar 2016
    Amended to allow for enrollment of more patients.
    11 Jul 2017
    Amended to prolong study period.

    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.
    Only twelve patients were treated.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29688262
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