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    Clinical Trial Results:
    Phase II trial of atezolizumab (anti-PD-L1) in the treatment of stage IIb-IV mycosis fungoides/sezary syndrome patients relapsed/refractory after a previous systemic treatment (PARCT)

    Summary
    EudraCT number
    		 2017-003680-35
    Trial protocol
    		 GB   DE   ES   AT   GR   IT  
    Global end of trial date
    18 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2023
    First version publication date
    30 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1652-CLTF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03357224
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer (EORTC)
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), 0032 27741044, regulatory@eortc.org
    Scientific contact
    Regulatory Affairs Department, European Organisation for Research and Treatment of Cancer (EORTC), 0032 27741044, regulatory@eortc.org
    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
    07 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the antitumor activity of atezolizumab for patients with refractory or relapsed advanced stages of mycosis fungoides and Sézary syndrome, assessed in terms of the overall response rate, according to EORTC-ISCL-USCLC criteria
    Protection of trial subjects
    The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 Trial assessing atezolizumab (anti-PD-L1) as treatment option for patients with mycosis fungoides (MF) /sezary syndrome (SS) having progressed under or after previous therapy. For this study, we invite patients suffering from MF and SS who have progressed after initial therapy or have failed to respond to previous therapy. MF and SS are cancers in which lymphocytes become malignant (cancerous) and affect the skin. In MF, the disease is generally limited to the skin, and people develop flat or raised areas on their skin where the lymphocytes have accumulated. Sometimes even larger aggregations of lymphocytes occur in the skin or lymph nodes, resulting in tumors. In SS, the skin is often reddened or itchy, and some abnormal lymphocytes circulate in the blood. Atezolizumab is already used to treat adults with a cancer that affects the bladder and the urinary system, called urothelial carcinoma, and a cancer that affects the lungs, called non-small cell lung cancer. In standard practice, the disease will be treated with conventional chemotherapy that unfortunately has a limited lasting benefit. In this study, we want to see if a new treatment option can optimize and improve response and make benefit last as long as possible. This new treatment option is immunotherapy, using atezolizumab (Tecentriq). Immunotherapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal cells that may help cancer cell grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Atezolizumab blocks a protein called PD-L1 (programmed death-ligand 1) from binding to its receptor found on the surface of lymphocytes. It helps to restore the immune activity of the body against the cancer. Atezolizumab is already used to treat adults with a cancer that affects the bladder and the urinary system, and the lungs.
    Evidence for comparator
    		 This is a single arm study. Two arms were provided in various parts of this report due to EUDRACT reporting system limitation.
    Actual start date of recruitment
    22 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    26
    EEA total number of subjects
    24
    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)
    10
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Following the occurrence of three toxic deaths, an urgent safety measure was put in place and the study was prematurely closed for accrual. At the time of closure, a total of 26 patients had been registered by 7 institutions in 7 countries between 23/10/2018 and 16/09/2019. Nine of the 26 patients did not meet the eligibility criteria.

    Pre-assignment
    Screening details
    		 •Male or female patients with diagnosis of CTCL (MF or SS) tumor stage IIB to IVB •Inadequate response or secondary treatment failure to at least 1 prior systemic therapy for CTCL according to treatment guidelines •Age ≥ 18 years old •WHO performance status 0-1 •Adequate bone marrow and organ function prior to receiving the study treatment

    Pre-assignment period milestones
    Number of subjects started
    		 26
    Number of subjects completed
    		 26

    Period 1
    Period 1 title
    Overall period - Full patient population
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 Atezolizumab
    Arm description
    		 Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezoluzimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria. Those patients for whom a clinical benefit is documentable at 1 year will be given the possibility to prolong the treatment for a maximum of two additional years unless a withdrawal criterion occurs earlier. In case of any additional adverse event grade 4 or higher is observed, the treatment will be permanently discontinued for all patients.

    Number of subjects in period 1
    		Atezolizumab
    Started
    26
    Completed
    4
    Not completed
    22
         Patient decision
    4
         Disease progression
    13
         Toxicity
    4
         Death not due to malignant disease/toxicity
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    		 Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria.

    Reporting group values
    		 Atezolizumab Total
    Number of subjects
    		 26 26
    Age categorical
    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)
    		 10 10
        From 65-84 years
    		 16 16
        85 years and over
    		 0 0
    Age continuous
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.77 ± 11.14 -
    Gender categorical
    Gender
    Units: Subjects
        Female
    		 14 14
        Male
    		 12 12
    Stage
    Disease stage
    Units: Subjects
        IB
    		 1 1
        IIB
    		 9 9
        IIIA
    		 3 3
        IIIB
    		 4 4
        IVA
    		 5 5
        IVB
    		 4 4
    WHO performance status
    Current WHO performance status
    Units: Subjects
        PS 0
    		 15 15
        PS 1
    		 11 11
    Diagnosis of CTCL
    Diagnosis of CTCL
    Units: Subjects
        Mycosis fungoides (MF)
    		 20 20
        Sézary Syndrome (SS)
    		 6 6
    Skin
    Skin stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        T1
    		 1 1
        T2
    		 6 6
        T3
    		 9 9
        T4
    		 10 10
    Node
    Node stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        N0
    		 14 14
        N1
    		 2 2
        N2
    		 1 1
        N3
    		 7 7
        Nx
    		 2 2
    Visceral
    Visceral stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        M0
    		 22 22
        M1
    		 4 4
    Blood
    Blood stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        B0
    		 13 13
        B1
    		 7 7
        B2
    		 6 6
    Node involvement at baseline (N3 vs. others)
    Node involvement at baseline (N3 vs. others)
    Units: Subjects
        No
    		 19 19
        Yes
    		 7 7
    mSWAT score
    Skin assessment is based on the mSWAT (Ref. 22, Ref. 23). This technique involves the direct assessment of the body-surface area (BSA) of each type of MF/SS lesion (palm plus fingers of the patient = approximately 1% BSA) in each of 12 areas of the body, multiplying the sum of the BSA of each lesion type by a weighting factor (patch, plaque and tumor) and generating a sum of the subtotals of each lesion subtype as shown below
    Units: Continuous score
        arithmetic mean (standard deviation)
    		 79.98 ± 48.53 -
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All registered patients. All 26 enrolled patients started atezolizumab in this study and were reviewed for eligibility by the project physician and approved by the study coordinator. Nine patients were considered to be ineligible. Major deviations included; -Retinoid treatment ongoing at start of study -Prostate adenocarcinoma diagnosed in 2018 -Targetrin treatment stopped at start of study treatment instead of 4 weeks before -Latent tuberculosis treated with rifampicin Uncontrolled diabetes -Uncontrolled diabetes with glycated hemoglobin above normal ranges -Tuberculosis infection -Tagretin and octagam (igg) washout not respected -No data on glucose level at baseline but patient is diabetic -Deep venous thrombosis and pulmonary embolism resolved 1 week prior to enrollment

    Subject analysis set title
    Per protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All registered patients who are eligible and have started atezolizumab treatment

    Subject analysis sets values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects
    26
    17
    Age categorical
    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)
    10
    7
        From 65-84 years
    16
    10
        85 years and over
    Age continuous
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.77 ± 11.14
    67.88 ± 8.12
    Gender categorical
    Gender
    Units: Subjects
        Female
    14
    10
        Male
    12
    7
    Stage
    Disease stage
    Units: Subjects
        IB
    1
    1
        IIB
    9
    7
        IIIA
    3
    1
        IIIB
    4
    3
        IVA
    5
    4
        IVB
    4
    1
    WHO performance status
    Current WHO performance status
    Units: Subjects
        PS 0
    15
    9
        PS 1
    11
    8
    Diagnosis of CTCL
    Diagnosis of CTCL
    Units: Subjects
        Mycosis fungoides (MF)
    20
    12
        Sézary Syndrome (SS)
    6
    5
    Skin
    Skin stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        T1
    1
    1
        T2
    6
    3
        T3
    9
    7
        T4
    10
    6
    Node
    Node stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        N0
    14
    10
        N1
    2
    0
        N2
    1
    0
        N3
    7
    5
        Nx
    2
    2
    Visceral
    Visceral stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        M0
    22
    16
        M1
    4
    1
    Blood
    Blood stage according to EORTC-ISCL-USCLC criteria
    Units: Subjects
        B0
    13
    8
        B1
    7
    5
        B2
    6
    4
    Node involvement at baseline (N3 vs. others)
    Node involvement at baseline (N3 vs. others)
    Units: Subjects
        No
    19
    12
        Yes
    7
    5
    mSWAT score
    Skin assessment is based on the mSWAT (Ref. 22, Ref. 23). This technique involves the direct assessment of the body-surface area (BSA) of each type of MF/SS lesion (palm plus fingers of the patient = approximately 1% BSA) in each of 12 areas of the body, multiplying the sum of the BSA of each lesion type by a weighting factor (patch, plaque and tumor) and generating a sum of the subtotals of each lesion subtype as shown below
    Units: Continuous score
        arithmetic mean (standard deviation)
    79.98 ± 48.53
    87.95 ± 55.49

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab
    Reporting group description
    		 Atezolizumab at a fixed dose of 1200 mg will be administered intravenously on Day 1 of each 21-day. cycle. Patients will receive atezoluzimab 1200 mg IV Q3w for 1 year since start of first protocol treatment administration unless clinically relevant disease progression or other withdrawal criteria.

    Subject analysis set title
    Intention-to-treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All registered patients. All 26 enrolled patients started atezolizumab in this study and were reviewed for eligibility by the project physician and approved by the study coordinator. Nine patients were considered to be ineligible. Major deviations included; -Retinoid treatment ongoing at start of study -Prostate adenocarcinoma diagnosed in 2018 -Targetrin treatment stopped at start of study treatment instead of 4 weeks before -Latent tuberculosis treated with rifampicin Uncontrolled diabetes -Uncontrolled diabetes with glycated hemoglobin above normal ranges -Tuberculosis infection -Tagretin and octagam (igg) washout not respected -No data on glucose level at baseline but patient is diabetic -Deep venous thrombosis and pulmonary embolism resolved 1 week prior to enrollment

    Subject analysis set title
    Per protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All registered patients who are eligible and have started atezolizumab treatment

    Primary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    Overall response rate (ORR) is defined as the proportion of patients who achieved complete response (CR) or partial response (PR) as best result up to maximum of 1 year from patient registration. The study was designed to reject the null hypothesis (H0: ORR=40%) with 90% power under the alternative hypothesis (H1: ORR=65%) using an exact binary test at 10% significance level 1-sided. A total of 29 eligible patients were needed. The drug would be considered to warrant further investigation if 16 or more out of 29 eligible patients who start treatment were responders (CR or PR). At the time of premature closure, there were only 17 eligible patients. Given the observed sample size , we assumed the same design; H0: ORR=40%, H1: ORR=65% and alpha=0.1. Based on this, with 78% power, at least 10 out of 17 eligible patients should be responders (CR or PR) for the drug to be considered worthwhile for further investigation (exact Type I error = 9.2% and power=78.7%).
    End point type
    Primary
    End point timeframe
    ORR is defined as the proportion of patients who achieved CR or PR as best result up to maximum of 1 year from patient registration. This is a single arm assessment. This endpoint was analysed in the per-protocol.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [1]
    17 [2]
    Units: Patients
        Success
    4
    3
        Failure
    22
    14
    Notes
    [1] - All registered patients who started atezolizumab.
    [2] - All eligible patients who started atezolizumab.
    Statistical analysis title
    		 Best overall response rate (CR/PR)
    Statistical analysis description
    All patients achieving CR or PR are counted as success. All other cases will be considered as failures. ORR will be calculated by summing the number of participants assessed as having a CR or PR and dividing this by the total number of patients who are eligible and started treatment. This is a single arm assessment. Two arms were provided due to EUDRACT reporting system limitation. This endpoint was analysed in the per-protocol population.
    Comparison groups
    Per protocol Population v Intention-to-treat Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    		 exact binary test
    Parameter type
    		 Proportion-Exact binomial 1-sided 90% CI
    Point estimate
    17.6
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 6.6
         upper limit
    		 -
    Notes
    [3] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation This analysis was performed in the per protocol population only

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Progression-free survival (PFS) is defined as the time from treatment start to the first date of progressive disease or death from any cause. For patients who did not progress or die, this endpoint will be censored on the date of last disease assessment
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) is defined as the time from treatment start to the first date of progressive disease or death from any cause.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [4]
    17 [5]
    Units: Months
        median (confidence interval 95%)
    3.0 (1.4 to 4.9)
    3.0 (1.4 to 4.9)
    Notes
    [4] - This is a single arm test - two arms were provided due to EUDRACT reporting system limitation
    [5] - This analysis was only performed in the per protocol population
    Statistical analysis title
    		 Secondary: PFS (per protocol population)
    Statistical analysis description
    Progression free survival (PFS) will be analyzed as time to event endpoints. Median PFS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
    Comparison groups
    Per protocol Population v Intention-to-treat Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    		 Kaplan-Meier
    Parameter type
    		 Median PFS estimate
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 4.9
    Notes
    [6] - This is a single arm assessment and PFS was performed only in the per protocol population. Two arms were provided due to EUDRACT reporting system limitation.
    Statistical analysis title
    		 Other specified: PFS (ITT population)
    Statistical analysis description
    This is a single arm assessment and this analysis was performed only in the intent-to-treat population. Two arms were provided due to EUDRACT reporting system limitation.
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    		 Kaplan-Meier
    Parameter type
    		 Median PFS estimate
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.4
         upper limit
    		 4
    Notes
    [7] - Progression free survival (PFS) will be analyzed as time to event endpoints. Median PFS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method. This is a single arm assessment. Two arms were provided due to EUDRACT reporting system limitation.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival (OS) is defined as the time from treatment start to the date of death from any cause. Patients who are still alive will be censored at the last date documented to be alive.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is defined as the time from treatment start to the date of death from any cause.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [8]
    17 [9]
    Units: Months
        median (confidence interval 95%)
    33.6 (16.5 to 999)
    33.6 (16.5 to 999)
    Notes
    [8] - This is a single arm test. Two arms are provided due to EUDRACT limitation. 999=estimate not reached
    [9] - This analysis was only performed in the per protocol population. 999=estimate not reached
    Statistical analysis title
    		 Secondary: OS(per protocol population)
    Statistical analysis description
    Median OS will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method.
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    		 Kaplan-Meier
    Parameter type
    		 Median OS estimate
    Point estimate
    33.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.5
         upper limit
    		 999
    Notes
    [10] - This is a single arm assessment and OS was performed only in the per protocol population. Two arms were provided due to EUDRACT reporting system limitation. Note 999= No estimate
    Statistical analysis title
    		 Other specified: OS(ITT population)
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    		 Kaplan-Meier
    Parameter type
    		 Median OS estimate
    Point estimate
    999
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 999
         upper limit
    		 999
    Notes
    [11] - Median OS was not reached. 999=estimate not reached

    Secondary: Time to response

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    End point title
    		 Time to response
    End point description
    Time to response is defined as the time from treatment start until the time measurement criteria for CR/PR (whichever is first recorded) are first met. For patients who did not reach CR/PR, this endpoint will be censored on the date of last disease assessment during treatment. Going off protocol treatment without achieving CR/PR is considered a competing risk. This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
    End point type
    Secondary
    End point timeframe
    Time to response is defined as the time from treatment start until the time measurement criteria for CR/PR (whichever is first recorded) are first met.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [12]
    17 [13]
    Units: Patient
        Complete or Partial response
    5
    4
        Competing event
    21
    13
    Notes
    [12] - This is a single arm assessment. Results were presented in the intention-to-treat population
    [13] - This is a single arm assessment. Results were presented in the per-protocol population
    No statistical analyses for this end point

    Secondary: Response duration

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    End point title
    		 Response duration
    End point description
    Response duration is defined as the interval from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that progressive disease is objectively documented. This endpoint is defined only in the subset of patients who achieve CR/PR. For patients who did not progress, this endpoint will be censored on the date of last disease assessment.
    End point type
    Secondary
    End point timeframe
    Response duration is defined as the interval from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that progressive disease is objectively documented.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [14]
    17 [15]
    Units: Months
        arithmetic mean (full range (min-max))
    12.63 (4.27 to 20.99)
    12.63 (4.27 to 20.99)
    Notes
    [14] - This is a single arm assessment. This endpoint was analysed only in the per-protocol population
    [15] - Amongst the 4 patients who achieved CR/PR in the per- protocol population, two patients progressed
    No statistical analyses for this end point

    Secondary: Time to next systemic treatment

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    End point title
    		 Time to next systemic treatment
    End point description
    Time to next systemic treatment is defined as the time from initiation of the current atezolizumab treatment until the time the next systemic treatment is recorded. For patients who did not have the record of next systemic treatment, this endpoint will be censored on the date of last adequate follow-up assessment.
    End point type
    Secondary
    End point timeframe
    Time to next systemic treatment is defined as the time from initiation of the current atezolizumab treatment until the time the next systemic treatment is recorded.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [16]
    17 [17]
    Units: Months
        median (confidence interval 95%)
    6.2 (3.1 to 14.8)
    5.9 (2.8 to 33.4)
    Notes
    [16] - Note: This is a single are study . Here, the analysis is performed in the ITT-population
    [17] - Note: This is a single are study . Here, the analysis is performed in the per- protocol population
    Statistical analysis title
    		 Secondary: Time to next systemic treatment-per pro
    Statistical analysis description
    Analysis will be performed in per-protocol population. Median Time to next systemic treatment will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method. Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    Method
    Parameter type
    		 Median time to next systemic treatment
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 33.4
    Notes
    [18] - Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations
    Statistical analysis title
    		 Other specified: Time to next systemic treatment
    Statistical analysis description
    Analysis will be performed in ITT population. Median Time to next systemic treatment will be estimated by the Kaplan Meier technique. The 95% confidence interval (CI) for the median will be calculated using the reflected CI method. Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    Method
    Parameter type
    		 Median time to next systemic treatment
    Point estimate
    6.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 14.8
    Notes
    [19] - Note: This is a single arm test - two arms were provided due to EUDRACT reporting system limitations. Analysis will be performed in ITT population.

    Other pre-specified: Best overall response(1 year)

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    End point title
    		 Best overall response(1 year)
    End point description
    All patients included in the study will be assessed for global response every 12 weeks (4 cycles), even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), relapse, early death or not evaluable. PD may be declared based on intermediate 6 weekly (every 2 cycles) blood and skin assessment. To be assigned a status of CR or PR the response must be confirmed by an assessment performed 4-8 weeks after the criteria for response are first met.
    End point type
    Other pre-specified
    End point timeframe
    Best overall response achieved (according to EORTC-ISCL-USCLC criteria) within 1 year from registration. This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [20]
    17 [21]
    Units: Patient
        Complete Response
    0
    0
        Partial response
    4
    3
        Stable disease
    10
    7
        Progression
    6
    5
        Not evaluable
    3
    1
        Early death
    3
    1
    Notes
    [20] - This is a single arm assessment. These results are based on the Intention-to-treat population.
    [21] - This is a single arm assessment. These results are based on the per-protocol population.
    No statistical analyses for this end point

    Other pre-specified: Best overall response(Follow-up)

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    End point title
    		 Best overall response(Follow-up)
    End point description
    All patients included in the study will be assessed for global response every 12 weeks (4 cycles), even if there is a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. Each patient will be assigned one of the following categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), relapse, early death or not evaluable. PD may be declared based on intermediate 6 weekly (every 2 cycles) blood and skin assessment. To be assigned a status of CR or PR the response must be confirmed by an assessment performed 4-8 weeks after the criteria for response are first met.
    End point type
    Other pre-specified
    End point timeframe
    Best overall response achieved (according to EORTC-ISCL-USCLC criteria) from registration throughout follow-up evaluations. This is a single arm assessment, presented separately in the per-protocol and Intention-to-treat populations.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [22]
    17 [23]
    Units: Patients
        Complete response
    1
    1
        Partial response
    4
    3
        Stable disease
    9
    6
        Progression
    6
    5
         Not evaluable
    3
    1
        Early death
    3
    1
    Notes
    [22] - This is a single arm assessment. Results were presented Intention-to-treat population
    [23] - This is a single arm assessment. Results were presented in the per-protocol population
    No statistical analyses for this end point

    Other pre-specified: Overall response rate (ORR)-ITT Population

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    End point title
    		 Overall response rate (ORR)-ITT Population
    End point description
    Standard disease assessment of tumour response status was performed every 2 cycles for skin and blood, and every 4 cycles for lymph nodes and visceral organs by local investigator according to EORTC/ISCL criteria allowing a global response call every 4 cycles. All patients achieving CR or PR are counted as success. All other cases will be considered as failures. ORR will be calculated by summing the number of participants assessed as having a CR or PR and dividing this by the total number of patients who are eligible and started treatment. This is a single arm assessment. This endpoint was analysed in the ITT-population.
    End point type
    Other pre-specified
    End point timeframe
    Overall response rate (ORR) is defined as the proportion of patients who achieved complete response (CR) or partial response (PR) as best result up to maximum of 1 year from patient registration.
    End point values
    		 Intention-to-treat Population Per protocol Population
    Number of subjects analysed
    26 [24]
    17 [25]
    Units: Subjects
        Success
    4
    3
        Failure
    22
    14
    Notes
    [24] - This is a single arm study. Here, ORR was assessed in the ITT population
    [25] - This is a single arm study. Here, ORR was assessed in the per-protocol population
    Statistical analysis title
    		 Other specified: ORR (ITT population)
    Statistical analysis description
    The study was designed to reject the null hypothesis (H0: ORR=40%) with 90% power under the alternative hypothesis (H1: ORR=65%) using an exact binary test at 10% significance level 1-sided. A total of 29 eligible patients who start treatment were required, among whom 16 or more needed to responders (CR or PR) to declare the study a success. Note: This is a single are study . The primary test will only be done in the per-protocol population.
    Comparison groups
    Intention-to-treat Population v Per protocol Population
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    Method
    		 Proportion-Exact binomial 1-sided 90% CI
    Parameter type
    		 Binomial proportion
    Point estimate
    15.4
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 6.8
         upper limit
    		 -
    Notes
    [26] - This is a single arm assessment. This endpoint was analysed here in the ITT population

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events, laboratory and physical abnormalities were collected till three months after the end of treatment. Afterwards, only treatment related AE are collected. For SAEs: all SAEs till 30 days after end of treatment; afterwards, only related SAEs
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (xx% AEs are reported as "other" and are not reported as not available from the list of SOC). AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, all AEs will be reported in non-SAE section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    ARM A - Atezolizumab
    Reporting group description
    		 -

    Serious adverse events
    		 ARM A - Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 26 (34.62%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    PYREXIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    PANCREATITIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    DRUG-INDUCED LIVER INJURY
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    MYALGIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    ABSCESS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SEPSIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ARM A - Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 26 (84.62%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    PROGRESS DISEASE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    NEOPLASM BENIGN
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Vascular disorders
    THROMBOEMBOLIC EVENT
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    General disorders and administration site conditions
    EDEMA FACE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    EDEMA LIMBS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    FATIGUE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 26 (23.08%)
         occurrences all number
    6
    FEVER
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    FLU LIKE SYMPTOMS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    4
    MULTI-ORGAN FAILURE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PAIN
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Immune system disorders
    ALLERGIC REACTION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Reproductive system and breast disorders
    IRREGULAR MENSTRUATION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    DYSPNEA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Psychiatric disorders
    DEPRESSION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    INSOMNIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    LABILITY OF AFFECT
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Investigations
    ALKALINE PHOSPHATASE INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    5
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    5
    LYMPHOCYTE COUNT DECREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    LIPASE INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    CPK INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    THYROID STIMULATING HORMONE INCREASED
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Nervous system disorders
    PARESTHESIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    HEADACHE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    ANEMIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    EOSINOPHILIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Eye disorders
    EYELID FUNCTION DISORDER
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    CATARACT
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    SENILE ECTROPIUM BOTH EYES
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Gastrointestinal disorders
    DENTAL CARIES
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    CONSTIPATION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    GASTROESOPHAGEAL REFLUX DISEASE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    DIARRHEA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    2
    MUCOSITIS ORAL
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PANCREAS, EXOCRINE ENZYME DEFICIENCY
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    NAUSEA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PANCREATITIS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    RECTAL HEMORRHAGE
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Hepatobiliary disorders
    DRUG-INDUCED LIVER INJURY
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    ERYTHRODERMA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    EZCEMA / CAPILARITIS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PAIN OF SKIN
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PRURITUS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    5
    SKIN HYPOPIGMENTATION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    RASH MACULO-PAPULAR
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    RASH ANTERIOR TRUNK
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Endocrine disorders
    HYPERTHYROIDISM
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    MYALGIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    LOMBALGIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    KNEE PAIN RIGHT
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    ARTHRALGIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    2
    MYOSITIS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PAIN IN EXTREMITY
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    Infections and infestations
    OTITIS MEDIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    PAPULOPUSTULAR RASH
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1
    SEPSIS
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    6
    SOFT TISSUE INFECTION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    2
    TUBERCULOSIS INFECTION
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    HYPOKALEMIA
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2020
    A scientific amendment (1652 protocol v7.0 20200701) took place on the 01/07/2020, due to a safety concern. The specific rationale for the amendment and its classification were: 1. The amendment followed an Urgent Safety Measures (USM) procedure. This Urgent Safety Measure procedure entailed the immediate closure of the trial recruitment on the 04/10/2019, following the occurrence of three sepsis-related deaths. Although the death event was deemed related to atezolizumab by the investigator only in one of these three cases, the sponsor in agreement with the study coordinators and the Chair of the EORTC CTCL Task Force decided to stop the recruitment. However, patients for whom a therapy effect was documentable were given the possibility to continue the treatment provided that they were properly informed about the USM by the investigator and they signed a PISIC addendum. An Urgent Safety Measures Letter has been sent to sites. 2. Treatment prolongation beyond 1 year for those patients who still benefit from atezolizumab at the treatment completion was extensively discussed with Study Coordinators and Roche. Given the strong ethical implications of stopping the treatment when clinical benefit is still documentable, especially in patients for whom not many therapeutic options are available, the company agreed on the extended drug supply. 3. Mandatory updates and changes concerning atezolizumab-related adverse events have been implemented in order to align with the newest IB (v 15) and addendum 2. 4. With the current sample size, this study is underpowered for the primary endpoint. Therefore a revised statistical analysis plan (SAP) provided details on the modification of the initial analysis plan of the EORTC protocol 1652 version 6 in light of the limited sample size. The revised SAP also includes some additional descriptive analysis of the efficacy and safety endpoints. 5. Addendum 2 v1.0 to PISIC v 3.0 for patient consent to stay on treatment beyond 1 year

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Oct 2019
    Following the occurrence of three toxic deaths, an urgent safety measure was put in place and further recruitment was closed. For patients already recruited, the treatment regimen was continued if considered beneficial to the patient as per investigator’s decision. This continuation remained subject to protocol treatment schedule and dosing and clinical evaluation procedures. If continuation was no longer deemed beneficial or the patient decided to discontinue the treatment, treatment was stopped. However, this patient remained part of the regular protocol follow-up regardless of further anti-cancer therapies.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    We did not meet the minimum number of responders needed to declare the trial as successful. A reason for this could be that the study was underpowered (78.7%) following premature closure. Only 17 eligible patients were enrolled instead of 29.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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