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    Clinical Trial Results:
    A phase II trial evaluating the safety and efficacy of the addition of concurrent anti-PD-1 nivolumab to standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B Non-Small Cell Lung Carcinoma.

    Summary
    EudraCT number
    		 2014-005097-11
    Trial protocol
    		 BE   ES   DE   NL  
    Global end of trial date
    14 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2021
    First version publication date
    05 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ETOP6-14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02434081
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 BMS number: CA209-208
    Sponsors
    Sponsor organisation name
    European Thoracic Oncology Platform
    Sponsor organisation address
    Effingerstr. 40, Bern, Switzerland, 3008
    Public contact
    ETOP Coordinating Office, ETOP, +41 31 511 94 00, regulatoryoffice@etop-eu.org
    Scientific contact
    ETOP Coordinating Office, ETOP, +41 31 511 94 00, regulatoryoffice@etop-eu.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
    14 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and efficacy of the concurrent nivolumab administration with standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC, as defined by the rate of grade ≥3 pneumonitis (CTCAE V4.0) 6 months post-radiotherapy and, if safety is proven, to assess the progression-free survival.
    Protection of trial subjects
    Informed consent for each patient was obtained prior to initiating any trial procedures. Patients have the right to withdraw consent for further trial participation at any time without having to specify the reason. Patients may only start nivolumab treatment if all adverse events from previous chemotherapy have resolved to grade <2 (with a few exceptions specified in the protocol). Because of the potential for clinically meaningful nivolumab-related AEs requiring early recognition and prompt intervention, management algorithms have been developed for suspected AEs of selected categories. Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the event is attributed to nivolumab). Also, specific criteria for treatment discontinuation apply, and instructions on how to deal with AEs according to their severity are provided. If a patient inadvertently becomes pregnant while on treatment with nivolumab, trial treatment will be stopped immediately for the patient and the event reported immediately. The trial may be discontinued early in parts or completely if the information on the product leads to doubt as to the benefit/risk ratio, by decision of ETOP or Trial Steering Committee, or at the suggestion of the IDMC based on the interim safety evaluations. The trial can be terminated at any time if the authorization and approval to conduct the trial is withdrawn by ethics committee or regulatory authority decision, insufficient accrual, emerging new data impacting the scientific value of the trial or ethical grounds.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 33 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Switzerland: 11
    Worldwide total number of subjects
    79
    EEA total number of subjects
    68
    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)
    44
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 82 eligible patients enrolled in the trial (79 patients in concurrent and 3 in sequential treatment). One of the patients enrolled under the protocol amendment, was initially under the original protocol, but was reconsidered and allowed to switch (assigned to the sequential treatment schedule).

    Pre-assignment
    Screening details
    		 A total of 95 patients, registered under the protocol amendment, were captured in iBiobank from 30th of September 2016 (enrollment of 1st patient) until the 6th of August 2018 (accrual suspension). Out of these, 13 were labeled with “Ineligible” or “Error” or “Draft” status.

    Period 1
    Period 1 title
    Concurrent CRT-Nivo (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is a single arm, open-label trial.

    Arms
    Arm title
    		 Concurrent CRT-Nivo
    Arm description
    		 Concurrent administration of chemoradiotherapy (CRT) and nivolumab (nivo)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558
    Other name
    MDX-1106
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The initial 4 doses of nivolumab were administered at 360 mg as intravenous infusion (approx. 30 minutes) every 3-weeks. The first 2 doses were administered concurrently with the last two chemotherapy cycles. Nivolumab was administered first and the infusion was promptly followed by a saline flush to clear the line of nivolumab before starting the chemotherapy infusion, no sooner than 30 minutes after completion of the nivolumab infusion. From dose 5 on, nivolumab was administered at 480 mg every 4 weeks for up to 1 year from start of nivolumab treatment, unless nivolumab treatment stopped earlier due to unacceptable toxicity, disease progression, withdrawal of consent or the trial is terminated by the sponsor. Dose 5 started 3 weeks after dose 4. Dose reductions or dose escalations of nivolumab were not permitted.

    Number of subjects in period 1
    		Concurrent CRT-Nivo
    Started
    79
    Completed
    31
    Not completed
    48
         Physician decision
    2
         Consent withdrawn by subject
    1
         Toxicity
    20
         Death
    2
         Progression
    20
         Protocol deviation
    1
         Patient died before start of treatment
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Concurrent CRT-Nivo
    Reporting group description
    		 -

    Reporting group values
    		 Concurrent CRT-Nivo Total
    Number of subjects
    		 79 79
    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
    Age at enrolment
    Units: years
        median (full range (min-max))
    		 62 (41 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 26 26
        Male
    		 53 53
    Smoking history
    Units: Subjects
        Current
    		 22 22
        Former
    		 54 54
        Never
    		 3 3
    ECOG PS at enrolment
    Units: Subjects
        Zero
    		 37 37
        One
    		 41 41
        Unkown/Missing
    		 1 1
    Histology
    Units: Subjects
        Non-squamous
    		 47 47
        Squamous
    		 28 28
        Missing
    		 4 4
    Stage
    Units: Subjects
        IIIA
    		 28 28
        IIIB
    		 50 50
        Missing
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Concurrent CRT-Nivo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients enrolled to the concurrent chemo-radio-nivo treatment.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who started the concurrent chemo-radio-nivo treatment.

    Subject analysis set title
    Primary efficacy cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary efficacy analysis cohort included the first 74 assessable patients on concurrent chemoradiotherapy who either completed 1 year of follow-up without an event or had a PFS event up to the 1-year time-point. This cohort did not take into consideration the two patients who died before the treatment started, one who withdrew 2.6 months after enrolment, and the last two enrolled patients who reached a 1-year follow-up at a later timepoint.

    Subject analysis sets values
    		 Concurrent CRT-Nivo Safety population Primary efficacy cohort
    Number of subjects
    79
    77
    74
    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
    Age at enrolment
    Units: years
        median (full range (min-max))
    62 (41 to 78)
    62 (41 to 78)
    62 (41 to 78)
    Gender categorical
    Units: Subjects
        Female
    26
    26
    23
        Male
    53
    51
    51
    Smoking history
    Units: Subjects
        Current
    22
    22
    21
        Former
    54
    52
    50
        Never
    3
    3
    3
    ECOG PS at enrolment
    Units: Subjects
        Zero
    37
    37
    34
        One
    41
    39
    39
        Unkown/Missing
    1
    1
    1
    Histology
    Units: Subjects
        Non-squamous
    47
    45
    43
        Squamous
    28
    28
    27
        Missing
    4
    4
    4
    Stage
    Units: Subjects
        IIIA
    28
    27
    25
        IIIB
    50
    49
    48
        Missing
    1
    1
    1

    End points

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    End points reporting groups
    Reporting group title
    Concurrent CRT-Nivo
    Reporting group description
    		 Concurrent administration of chemoradiotherapy (CRT) and nivolumab (nivo)

    Subject analysis set title
    Concurrent CRT-Nivo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients enrolled to the concurrent chemo-radio-nivo treatment.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who started the concurrent chemo-radio-nivo treatment.

    Subject analysis set title
    Primary efficacy cohort
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The primary efficacy analysis cohort included the first 74 assessable patients on concurrent chemoradiotherapy who either completed 1 year of follow-up without an event or had a PFS event up to the 1-year time-point. This cohort did not take into consideration the two patients who died before the treatment started, one who withdrew 2.6 months after enrolment, and the last two enrolled patients who reached a 1-year follow-up at a later timepoint.

    Primary: PFS (primary efficacy cohort)

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    End point title
    		 PFS (primary efficacy cohort) [1]
    End point description
    The censoring date for PFS was the date of the last tumour assessment without event. Estimates refer to 1-year PFS.
    End point type
    Primary
    End point timeframe
    Progression-free survival (PFS) is defined at the time from first chemotherapy cycle until a documented progression of disease or death if no documented progression had occurred.
    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: Based on the Kaplan-Meier method, the PFS at 1-year was 50.0% (95% CI: 39.9% – 60.1%). Thus, the null hypothesis of a 1-year PFS rate of less than or equal to 45% could not be rejected (exact binomial test p=0.23).
    End point values
    		 Primary efficacy cohort
    Number of subjects analysed
    74
    Units: Percentage
        number (confidence interval 95%)
    50 (39.9 to 60.1)
    No statistical analyses for this end point

    Primary: Rate of pts without grade≥3 pneumonitis 6-months post-RT

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    End point title
    		 Rate of pts without grade≥3 pneumonitis 6-months post-RT [2]
    End point description
    End point type
    Primary
    End point timeframe
    Grade ≥3 pneumonitis (CTCAE V4.0) observed any time during 6 months from end of radiotherapy.
    Notes
    [2] - 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: This endpoint provides the number of patients (rate) without grade≥3 pneumonitis 6-months post-radiotherapy. These were 71 out of 77, thus a rate of 92.2%. The corresponding safety hypothesis has been tested in an interim analysis and safety of the treatment was proven there.
    End point values
    		 Safety population
    Number of subjects analysed
    77
    Units: Pts w/o grade≥3 pneumonitis 6-m post-RT
    71
    No statistical analyses for this end point

    Secondary: TFP3

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    End point title
    		 TFP3
    End point description
    End point type
    Secondary
    End point timeframe
    Time to first pneumonitis of grade ≥3 (TFP3) is defined as time from the first chemotherapy cycle until first documented pneumonitis of grade ≥3.
    End point values
    		 Safety population
    Number of subjects analysed
    77
    Units: Percentage
        number (confidence interval 95%)
    87.0 (76.4 to 93.0)
    No statistical analyses for this end point

    Secondary: ORR

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    End point title
    		 ORR
    End point description
    End point type
    Secondary
    End point timeframe
    For the calculation of objective response rate (ORR) the time from first chemotherapy cycle until partial or complete response was considered.
    End point values
    		 Concurrent CRT-Nivo
    Number of subjects analysed
    79
    Units: No. of subjects with objective response
    58
    No statistical analyses for this end point

    Secondary: TTF

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    End point title
    		 TTF
    End point description
    End point type
    Secondary
    End point timeframe
    Time to treatment failure (TTF) is defined as time from first chemotherapy cycle to discontinuation of treatment for any reason, including disease progression, toxicity, withdrawal, lost to follow-up or death.
    End point values
    		 Concurrent CRT-Nivo
    Number of subjects analysed
    79
    Units: Months
        median (confidence interval 95%)
    9.2 (6.4 to 12.4)
    No statistical analyses for this end point

    Secondary: OS

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    End point title
    		 OS
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is defined as time from first chemotherapy cycle until death from any cause.
    End point values
    		 Concurrent CRT-Nivo
    Number of subjects analysed
    79 [3]
    Units: Months
        median (confidence interval 95%)
    38.8 (26.8 to 9999)
    Notes
    [3] - Upper 95%CI is Not Estimable (NE). Since letters are not accepted, a value of "9999" is entered.
    No statistical analyses for this end point

    Secondary: Toxicity

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    End point title
    		 Toxicity
    End point description
    Adverse events classified according to CTCAE version 4.
    End point type
    Secondary
    End point timeframe
    Time from first chemotherapy cycle until 100 days after the final dose of nivolumab (regardless of whether the adverse events were considered related to the trial treatment).
    End point values
    		 Safety population
    Number of subjects analysed
    77
    Units: No. of adverse events
    780
    No statistical analyses for this end point

    Secondary: PFS (full concurrent CRT-Nivo cohort)

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    End point title
    		 PFS (full concurrent CRT-Nivo cohort)
    End point description
    The censoring date for PFS was the date of the last tumour assessment without event. Estimates refer to 1-year PFS.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) is defined at the time from first chemotherapy cycle until a documented progression of disease or death if no documented progression had occurred.
    End point values
    		 Concurrent CRT-Nivo
    Number of subjects analysed
    79
    Units: Percentage
        number (confidence interval 95%)
    53.7 (42.0 to 64.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected up to 100 days after the final dose of nivolumab, regardless of whether they were considered related to the trial treatment.
    Adverse event reporting additional description
    After the last dose, only AEs considered possibly related to nivolumab by the Investigator had to be reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Safety cohort
    Reporting group description
    		 -

    Serious adverse events
    		 Safety cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 77 (48.05%)
         number of deaths (all causes)
    37
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pericarditis
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Ataxia
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Autoimmune disorder
    Additional description: The main cause of death is not certain. Immune-mediated myocarditis vs pulmonary embolism are not excluded.
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Gastrointestinal disorders
    Esophagitis
         subjects affected / exposed
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Esophageal fistula
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Esophageal varices hemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    13 / 77 (16.88%)
         occurrences causally related to treatment / all
    13 / 13
         deaths causally related to treatment / all
    1 / 1
    Dyspnea
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial stricture
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 77 (98.70%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    38 / 77 (49.35%)
         occurrences all number
    38
    Fever
         subjects affected / exposed
    15 / 77 (19.48%)
         occurrences all number
    15
    Pain
         subjects affected / exposed
    13 / 77 (16.88%)
         occurrences all number
    13
    Flu like symptoms
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    34 / 77 (44.16%)
         occurrences all number
    34
    Productive cough
         subjects affected / exposed
    31 / 77 (40.26%)
         occurrences all number
    31
    Dyspnea
         subjects affected / exposed
    26 / 77 (33.77%)
         occurrences all number
    26
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 77 (16.88%)
         occurrences all number
    13
    Anxiety
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Investigations
    Lipase increased
         subjects affected / exposed
    9 / 77 (11.69%)
         occurrences all number
    9
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 77 (11.69%)
         occurrences all number
    9
    Platelet count decreased
         subjects affected / exposed
    9 / 77 (11.69%)
         occurrences all number
    9
    White blood cell decreased
         subjects affected / exposed
    9 / 77 (11.69%)
         occurrences all number
    9
    Creatinine increased
         subjects affected / exposed
    8 / 77 (10.39%)
         occurrences all number
    8
    Serum amylase increased
         subjects affected / exposed
    8 / 77 (10.39%)
         occurrences all number
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Weight gain
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Dermatitis radiation
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 77 (14.29%)
         occurrences all number
    11
    Headache
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Tremor
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Stroke
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    37 / 77 (48.05%)
         occurrences all number
    37
    Neutrophil count decreased
         subjects affected / exposed
    27 / 77 (35.06%)
         occurrences all number
    27
    Febrile neutropenia
         subjects affected / exposed
    7 / 77 (9.09%)
         occurrences all number
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    26 / 77 (33.77%)
         occurrences all number
    26
    Diarrhea
         subjects affected / exposed
    12 / 77 (15.58%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    10 / 77 (12.99%)
         occurrences all number
    10
    Esophageal pain
         subjects affected / exposed
    7 / 77 (9.09%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    8 / 77 (10.39%)
         occurrences all number
    8
    Mucositis oral
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Esophagitis
         subjects affected / exposed
    24 / 77 (31.17%)
         occurrences all number
    24
    Nausea
         subjects affected / exposed
    20 / 77 (25.97%)
         occurrences all number
    20
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    12 / 77 (15.58%)
         occurrences all number
    12
    Dry skin
         subjects affected / exposed
    10 / 77 (12.99%)
         occurrences all number
    10
    Rash acneiform
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Rash maculo-papular
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Alopecia
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 77 (5.19%)
         occurrences all number
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Hyperthyroidism
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    9 / 77 (11.69%)
         occurrences all number
    9
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    8 / 77 (10.39%)
         occurrences all number
    8
    Upper respiratory infection
         subjects affected / exposed
    7 / 77 (9.09%)
         occurrences all number
    7
    Lung infection
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    5 / 77 (6.49%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    14 / 77 (18.18%)
         occurrences all number
    14
    Hypomagnesaemia
         subjects affected / exposed
    6 / 77 (7.79%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2016
    Under first amendment there would still be two treatment schedules in the trial, a concurrent and a sequential, as in the original protocol. The amendment differed from the original in the sense that, under both treatment schedules, administration of nivolumab would start together with radiotherapy.
    04 Jul 2017
    Under second amendment there would be only the concurrent treatment schedule in the trial.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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