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    Clinical Trial Results:
    Adoptive cell therapy across cancer diagnoses

    Summary
    EudraCT number
    		 2017-002323-25
    Trial protocol
    		 DK  
    Global end of trial date
    04 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AA1720
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03296137
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev Hospital
    Sponsor organisation address
    Ib Juuls vej 1, Herlev, Denmark, 2730
    Public contact
    Principal investigator, Center for cancer immune therapy, +45 36686467, anders.kverneland@regionh.dk
    Scientific contact
    Principal investigator, Center for cancer immune therapy, +45 36686467, anders.kverneland@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
    04 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective is to determine the feasibility and safety of adoptive cell therapy in combination with checkpoint inhibition across different metastatic solid cancers.
    Protection of trial subjects
    Patients were constantly monitored for safety and general condition. Treatable conditions where treated when appropiate.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    22
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Metastatic cancer disease Exhausted standard therapies Good performance status and vital organ function

    Pre-assignment
    Screening details
    		 Metastasis avaliable for safe resection. Acceptable vital organ function including kidney, lung, liver and heart. Acceptable performance status.

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

    Arms
    Arm title
    		 TIL therapy
    Arm description
    		 The study design included: 1) ipilimumab (3 mg/kg) 2 weeks before tumor removal 2) Surgical resection of tumor tissue for expansion of tumor-infiltrating lymphocytes (TILs) in vitro 3) Conditioning chemotherapy with cyclophosphamide (60 mg/kg x 2) and fludarabine-phosphate (25 mg/m2 x 5) 4) Infusion of in vitro expanded TILs 5) Nivolumab (3 mg/kg) at day -2, 12, 26 and 40 relative to TIL infusion 6) Stimulation with low dose IL-2 (2 MIU x1 s.c.) for 14 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Sendoxan
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg x 2 at day -7 and -6 relative to TIL infusion

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Yervoy
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg at least 14 days before surgical tumor resection for TIL generation

    Investigational medicinal product name
    Fludarabine phophate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 x 5 at day -5, -4, -3, -2 and -1 relative to TIL infusion.

    Investigational medicinal product name
    Aldesleukin
    Investigational medicinal product code
    Other name
    Interleukin-2
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 million international units daily at day 0 to day 13 relative to TIL infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Opdivo
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg at day -2, 12, 26 and 40 relative to TIL infusion

    Investigational medicinal product name
    Tumor infiltration lymphocytes
    Investigational medicinal product code
    Other name
    TILs, adoptive cell therapy, autologous cell product
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The cell product is generated from in vitro expansion of autologous tumor infiltrating lymphocytes. The expansion consists of an initial step with IL-2 media and a second step with IL-2, anti-CD3 and feeder cells. between 5 x 10e9 and 150 x 10e9 cells are infused into the patient.

    Number of subjects in period 1
    		TIL therapy
    Started
    25
    Completed
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TIL therapy
    Reporting group description
    		 -

    Reporting group values
    		 TIL therapy Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
        39-66
    		 25 25
    Age continuous
    Units: years
        median (full range (min-max))
    		 54 (39 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    TIL therapy
    Reporting group description
    		 The study design included: 1) ipilimumab (3 mg/kg) 2 weeks before tumor removal 2) Surgical resection of tumor tissue for expansion of tumor-infiltrating lymphocytes (TILs) in vitro 3) Conditioning chemotherapy with cyclophosphamide (60 mg/kg x 2) and fludarabine-phosphate (25 mg/m2 x 5) 4) Infusion of in vitro expanded TILs 5) Nivolumab (3 mg/kg) at day -2, 12, 26 and 40 relative to TIL infusion 6) Stimulation with low dose IL-2 (2 MIU x1 s.c.) for 14 days

    Subject analysis set title
    TIL therapy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The protocol is a phase I-II clinical trial andthe results will be analysed in a qualitative manner.

    Primary: Tolerability and feasibility of TIL therapy with CPI addition

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    End point title
    		 Tolerability and feasibility of TIL therapy with CPI addition [1]
    End point description
    Patients in which the TIL expansion and following therapy was possible
    End point type
    Primary
    End point timeframe
    Whole trial period
    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 clinical trial is an exploratory phase I-II clinical trial with a relative low number of patients. The stastical power to analyse such a small and heterogenous data set is very limited and the analysis will instead be qualiative.
    End point values
    		 TIL therapy
    Number of subjects analysed
    31 [2]
    Units: 25
    25
    Notes
    [2] - Unsuccesful in 6 patients that underwent surgery
    No statistical analyses for this end point

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    6 months after treatment
    End point values
    		 TIL therapy
    Number of subjects analysed
    25
    Units: 25
        PR
    2
        SD
    5
        PD
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of therapy until trial discontinuation
    Adverse event reporting additional description
    CTCAE v4
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    TIL therapy
    Reporting group description
    		 -

    Serious adverse events
    		 TIL therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 25 (36.00%)
         number of deaths (all causes)
    25
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
    Additional description: Refractory causes by alloimmunization
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chylos
    Additional description: Swelling of the neck due to surgical removal of metastastic lymph node
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
    Additional description: In vena jugularis after insertion of central venous catheter
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Colitis
    Additional description: Immune therapy related adverse event
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Cough
    Additional description: Fever and cough. Spontanous remission
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bilirubin excretion disorder
    Additional description: Due to progression in liver metastases
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
    Additional description: Acute reaction and T-cell infusion. Transfered to ICU for intubation. Returned after 4 days.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Cystitis
    Additional description: Infection after insertion of ureteric stent insertion.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Addison's disease
    Additional description: Addisons crisis. Patient with adenocorticocarcinoma and in mitotane therapy.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Febrile neutropenia
    Additional description: After discharge recurrent neutropenia and onset of fever
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
    Additional description: After initial discharge after TIL therapy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 TIL therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    Vascular disorders
    Thrombosis
    Additional description: In central venous catheter
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    25 / 25 (100.00%)
         occurrences all number
    27
    Thrombocytopenia
         subjects affected / exposed
    22 / 25 (88.00%)
         occurrences all number
    22
    Anaemia
         subjects affected / exposed
    22 / 25 (88.00%)
         occurrences all number
    22
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    6 / 25 (24.00%)
         occurrences all number
    6
    Performance status decreased
         subjects affected / exposed
    9 / 25 (36.00%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Immune system disorders
    Febrile neutropenia
    Additional description: Due to cell therapy and IL-2 therapy
         subjects affected / exposed
    16 / 25 (64.00%)
         occurrences all number
    18
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    4
    Hepatobiliary disorders
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Renal and urinary disorders
    Hyponatraemia
    Additional description: Cyclophosphamide induced
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Infections and infestations
    Infection in an immunocompromised host
         subjects affected / exposed
    6 / 25 (24.00%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The patients are late stage cancer patients with many accompanying comorbidities. The study design consists of many different drugs and the individual contribution to effacacy and safety is difficult to assess.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34607899
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