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    Clinical Trial Results:
    Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with Non-Small Cell Lung Cancer (NSCLC) after radiochemotherapy (RCT)

    Summary
    EudraCT number
    		 2008-002130-30
    Trial protocol
    		 DE  
    Global end of trial date
    07 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 May 2020
    First version publication date
    16 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NSCLC-TKD/IL-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Technische Universität München, Fakultät für Medizin
    Sponsor organisation address
    Ismaninger Str. 22, München, Germany, 81675
    Public contact
    Iniv. Prof. Dr. med. Stephanie Combs, Klinikum rechts der Isar der TUM Klinik für RadioOnkologie und Strahlenterapie, 0049 (0)8941404501, StephanieElisabeth.Combs@mri.tum.de
    Scientific contact
    Iniv. Prof. Dr. med. Stephanie Combs, Klinikum rechts der Isar der TUM Klinik für RadioOnkologie und Strahlenterapie, +49 89 4140 4501, StephanieElisabeth.Combs@mri.tum.de
    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
    26 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to examine whether an adjuvant treatment with TKD/IL-2-activated, patient-derived NK cells following definitive RCT is feasible and effective. Comparison of progression-free survival between treatment and control group A control arm with standard radiochemotherapy (Cisplatin/Vinorelbine) is part of this study, because Pfister et al (2007) could demonstrate that lung cancer patients with an Hsp70 membrane expression had a poorer clinical outcome with respect to overall survival when compared to their Hsp70 membrane counterparts. Therefore, all historic data on overall survival of lung cancer patients are the result of a mixture of Hsp70 positive and negative patients and median overall survival of Hsp70 positive lung cancer patients is not known.
    Protection of trial subjects
    The conduct of this clinical study met the local legal and regulatory requirements. The study was conducted in accordance the ethical principles of Good Clinical Practice (GCP). Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. The study was regularly monitored by the Sponsor and all investigators connected to the study were GCP trained.
    Background therapy
    		 Standard of care.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pre-screening processes were in place for all patients. 16 patients were randomised between 27.11.2014 and 08.08.2016.

    Pre-assignment
    Screening details
    		 Patients must have all screening evaluations performed prior to the first dose of study drug and must meet all inclusion and none of the exclusion criteria. The patients must be thoroughly informed about all aspects of the study, all evaluations as required per protocol and all regulatory requirements for informed consent.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TKD/IL-2 Activated NK_Cells
    Arm description
    		 The group of Hsp70 positive subjects received Hsp70-peptide TKD/IL-2 activated, autologous NK cells (somatic cell therapy, plasma derived medicinal product, IMP) subsequent to standard RCT. Patients underwent leukapheresis of 3-4 hours before each treatment cycle to collect lymphocytes. A defined number of lymphocytes were activated for 3-5 days with GMP grade Hsp70-peptide TKD (Bachem) plus low dose IL-2 (100 IU/ml; Proleukin, Chiron) at a cell density of 10x106 cells. Patients were to be treated with NK therapy every 2-6 weeks on study visits (V) 2, V3, V4, and V5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TKD_NK
    Investigational medicinal product code
    Other name
    TKD/IL-2 Activated NK_Cells
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The group of Hsp70 positive subjects received Hsp70-peptide TKD/IL-2 activated, autologous NK cells (somatic cell therapy, plasma derived medicinal product, IMP) subsequent to standard RCT. Patients underwent leukapheresis of 3-4 hours before each treatment cycle to collect lymphocytes. A defined number of lymphocytes were activated for 3-5 days with GMP grade Hsp70-peptide TKD (Bachem) plus low dose IL-2 (100 IU/ml; Proleukin, Chiron) at a cell density of 10x106 cells. On day 3-5 the TKD/IL-2 activated, autologous NK cells were washed twice in Ringer’s Lactate solution, re-suspended in 500 ml of Ringer’s Lactate/0.1%HSA and re-infused into the patient intravenously over 30-60 min using a stem cell infusion set. Patients were to be treated with NK therapy every 2-6 weeks on study visits (V) 2, V3, V4, and V5.

    Arm title
    		 Standard RCT
    Arm description
    		 The group of Hsp70 positive subjects received best supportive care following their standard RCT.
    Arm type
    		 Best supportive care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		TKD/IL-2 Activated NK_Cells Standard RCT
    Started
    8
    8
    Completed
    4
    4
    Not completed
    4
    4
         Study closed
    1
    -
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    -
    1
         Tumor progression
    1
    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
    		 16 16
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized subjects who received at least one dose of sudy mdeication.

    Subject analysis sets values
    		 ITT
    Number of subjects
    15
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ( 7.0 )
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    8

    End points

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    End points reporting groups
    Reporting group title
    TKD/IL-2 Activated NK_Cells
    Reporting group description
    		 The group of Hsp70 positive subjects received Hsp70-peptide TKD/IL-2 activated, autologous NK cells (somatic cell therapy, plasma derived medicinal product, IMP) subsequent to standard RCT. Patients underwent leukapheresis of 3-4 hours before each treatment cycle to collect lymphocytes. A defined number of lymphocytes were activated for 3-5 days with GMP grade Hsp70-peptide TKD (Bachem) plus low dose IL-2 (100 IU/ml; Proleukin, Chiron) at a cell density of 10x106 cells. Patients were to be treated with NK therapy every 2-6 weeks on study visits (V) 2, V3, V4, and V5.

    Reporting group title
    Standard RCT
    Reporting group description
    		 The group of Hsp70 positive subjects received best supportive care following their standard RCT.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized subjects who received at least one dose of sudy mdeication.

    Primary: Progression free survival - PFS

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    End point title
    		 Progression free survival - PFS
    End point description
    End point type
    Primary
    End point timeframe
    From time of randomisation to 18 months follow-up. The point estimate of PFS is given for 12 months.
    End point values
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Number of subjects analysed
    7 [1]
    8
    Units: percent
        number (confidence interval 95%)
    67 (19 to 90)
    33 (5 to 68)
    Notes
    [1] - One patient excluded from ITT
    Statistical analysis title
    		 Comparison of PFS
    Statistical analysis description
    One-sided log-rank test
    Comparison groups
    TKD/IL-2 Activated NK_Cells v Standard RCT
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 3.45

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    All patients survived 18 months after treatment
    End point type
    Secondary
    End point timeframe
    From time of randomisation to 18 months follow-up.
    End point values
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Number of subjects analysed
    7 [2]
    8
    Units: patients
    7
    8
    Notes
    [2] - One patient excluded from ITT
    No statistical analyses for this end point

    Secondary: Response to treatment

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    End point title
    		 Response to treatment
    End point description
    End point type
    Secondary
    End point timeframe
    From time of randomisation to 18 months follow-up.
    End point values
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Number of subjects analysed
    6 [3]
    8
    Units: Patients
        irCR
    1
    0
        irPR
    1
    1
        irSD
    1
    1
        irPD
    3
    5
    Notes
    [3] - One patient excluded from ITT, one patient dropped out before V3
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    		 Quality of life
    End point description
    Quality of life is measured by the QLQ-C30 score
    End point type
    Secondary
    End point timeframe
    Visit 1 to Visit 9.
    End point values
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Number of subjects analysed
    7 [4]
    8
    Units: score
    arithmetic mean (standard deviation)
        Visit 1
    67.4 ( 16.7 )
    74.2 ( 21.5 )
        Visit 6
    92.5 ( 4.1 )
    82.6 ( 14.6 )
        Visit 7
    87.0 ( 6.2 )
    75.0 ( 18.8 )
        Visit 8
    77.8 ( 19.6 )
    72.6 ( 26.3 )
        Visit 9
    84.5 ( 9.8 )
    78.4 ( 20.3 )
    Notes
    [4] - One patient was excluded from the ITT set
    No statistical analyses for this end point

    Secondary: NK activation

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    End point title
    		 NK activation
    End point description
    Percent increase of CD94+ NK cells considering successful re-infusions only.
    End point type
    Secondary
    End point timeframe
    Visit 2, visit 3, visit 4, visit 5
    End point values
    		 ITT
    Number of subjects analysed
    Units: Percent increase of CD94+ NK cells
    arithmetic mean (standard deviation)
        Visit 2
    100 ( 36 )
        Visit 3
    143 ( 109 )
        Visit 4
    103 ( 43 )
        Visit 5
    116 ( 56 )
    No statistical analyses for this end point

    Secondary: Toxicity

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    End point title
    		 Toxicity
    End point description
    Toxicity measured according to NCI CTCAE v4.0
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Number of subjects analysed
    7 [5]
    8
    Units: Patients
        Grade 3
    3
    1
    Notes
    [5] - One patient excluded from ITT
    Statistical analysis title
    		 Toxicity
    Statistical analysis description
    Comparison of number of patients with toxicity throughout the study between the two study groups. Only toxicities of grade 3 were observed.
    Comparison groups
    TKD/IL-2 Activated NK_Cells v Standard RCT
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were documented in the timeframe from signed informed consent till the end of the follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    TKD/IL-2 Activated NK_Cells
    Reporting group description
    		 The group of Hsp70 positive subjects received Hsp70-peptide TKD/IL-2 activated, autologous NK cells (somatic cell therapy, plasma derived medicinal product, IMP) subsequent to standard RCT. Patients underwent leukapheresis of 3-4 hours before each treatment cycle to collect lymphocytes. A defined number of lymphocytes were activated for 3-5 days with GMP grade Hsp70-peptide TKD (Bachem) plus low dose IL-2 (100 IU/ml; Proleukin, Chiron) at a cell density of 10x106 cells. Patients were to be treated with NK therapy every 2-6 weeks on study visits (V) 2, V3, V4, and V5.

    Reporting group title
    Standard RCT
    Reporting group description
    		 The group of Hsp70 positive subjects received best supportive care following their standard RCT.

    Serious adverse events
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (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
    local swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Swelling face
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (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
    		 TKD/IL-2 Activated NK_Cells Standard RCT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    3 / 8 (37.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    metastatic pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Lymphadenectomy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Performance status decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Pericardial effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Burning mouth syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Coeliac disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    sensation of heaviness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    3
    Syphilis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0

    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.
    Based of the slower than expected recruitment and current standard of care for NSCLC as recommended at this time (e.g. NCCN guidelines, 2018) the clinical trial was terminated prematurely.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30747241
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