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    Clinical Trial Results:
    A randomised open-label phase II trial of consolidation with nivolumab and ipilimumab in limited-stage SCLC after chemo-radiotherapy

    Summary
    EudraCT number
    		 2013-002609-78
    Trial protocol
    		 BE   ES   FR   DE   NL   GB  
    Global end of trial date
    03 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ETOP/IFCT 4-12/CA184-310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02046733
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IFCT: IFCT 4-12
    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
    25 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate if patients treated with chemo-radiotherapy and prophylactic cranial irradiation followed by consolidation treatment (nivolumab plus ipilimumab) have a better outcome in terms of progression-free survival and overall survival, compared to patients treated with chemo-radiotherapy and prophylactic cranial irradiation without consolidation treatment.
    Protection of trial subjects
    The Investigator will ensure that this study is conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater protection to the patient. For studies conducted in the EU/EEA countries, the Investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC). All protocols and the patient informed consent forms must have the approval of a properly constituted committee or committees responsible for approving clinical trials. Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities (if required), the investigator shall implement the protocol modifications. Protocol modifications for urgent safety matters may be directly implemented following the instructions of ETOP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 1 Years
    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: 61
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 78
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Australia: 6
    Worldwide total number of subjects
    222
    EEA total number of subjects
    197
    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)
    139
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From December 2015 to April 2019, a total of 222 patients were enrolled to the chemotherapy phase under protocol AM1 coming from 52 centers of 8 countries. Overall, 153 patients were randomized under AM1 and constitute the ITT cohort of the efficacy analysis (145 of those were enrolled under AM1 and 8 were enrolled under the original protocol).

    Pre-assignment
    Screening details
    		 302 patients registered in ETOP iBiobank up to 30 April 2019. Of note, these patients are not all assessed for eligibility, since it was not mandatory to enter in database all patients assesses. Out of 302 patients, 38 did not enrolled (23 ineligible, 15 error). In total 222 patients enrolled under protocol AM1 and of them 153 randomized under AM1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab and Ipilimumab
    Arm description
    		 Induction phase: Nivolumab followed (on the same day) by Ipilimumab, for 4 cycles. Maintenance phase: Nivolumab, for a maximum of 12 months from the start of the maintenance phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    BMS-936558
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction phase (to start within 6-8 weeks (42-56 days) after the start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation): Nivolumab at a dose of 1 mg/kg i.v. over a period of 30 minutes, for 4 cycles. Maintenance phase (to start 3 weeks (21days) after the last IMP doses of induction phase): Nivolumab at a dose of 240 mg i.v. over a period of 30 minutes, once every 2 weeks (+/- 2 days, without dosing delay), for a maximum of 12 months from the start of maintenance. Patients should not be dosed less than 12 days from the previous dose of nivolumab.

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction phase (to start within 6-8 weeks (42-56 days) after the start of chemotherapy cycle 4, and not more than 2 weeks (14 days) after the date of randomisation): Ipilimumab at a dose of 3 mg/kg i.v. over a period of 90 minutes once every 3 weeks (+/- 3 days, without dosing delay), for 4 cycles

    Arm title
    		 Observation
    Arm description
    		 No further treatment after chemo-radiotherapy and PCI.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Nivolumab and Ipilimumab Observation
    Started
    78
    75
    Completed
    8
    33
    Not completed
    70
    42
         On treatment
    5
    -
         Physician decision
    4
    -
         Patient decision
    7
    -
         On 'treatment'
    -
    4
         Adverse event, non-fatal
    36
    -
         Death
    3
    -
         Progression
    15
    31
         Never initiated 'treatment visits'
    -
    6
         unspecified reason
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 222 patients enrolled under protocol AM1, 145 patients were eligible for randomization under AM1. In total 153 patients were randomized under protocol AM1 (145 enrolled under AM1 and 8 enrolled under original protocol) (78 in experimental arm and 75 in observation arm).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab and Ipilimumab
    Reporting group description
    		 Induction phase: Nivolumab followed (on the same day) by Ipilimumab, for 4 cycles. Maintenance phase: Nivolumab, for a maximum of 12 months from the start of the maintenance phase.

    Reporting group title
    Observation
    Reporting group description
    		 No further treatment after chemo-radiotherapy and PCI.

    Reporting group values
    		 Nivolumab and Ipilimumab Observation Total
    Number of subjects
    		 78 75 153
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 57 48 105
        From 65-84 years
    		 21 27 48
        85 years and over
    		 0 0 0
    Age continuous
    Age (years at enrolment)
    Units: years
        median (full range (min-max))
    		 61.1 (37.7 to 83.2) 61.9 (38.6 to 77.3) -
    Gender categorical
    Units: Subjects
        Female
    		 28 33 61
        Male
    		 50 42 92
    Smoking history
    Units: Subjects
        Current
    		 27 25 52
        Former (≥100 cigarettes in the past/whole life)
    		 51 49 100
        Never (0-99 cigarettes/whole life)
    		 0 1 1
    ECOG performance status (at randomization)
    Measure Description: 0: Fully active, able to carry on all pre-disease performance without restriction, 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2: Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours, 3: Capable of only limited self-care; confined to bed or chair more than 50% of waking hours, 4: Completely disabled; cannot carry on any self-care; totally confined to bed or chair, 5: Dead
    Units: Subjects
        zero
    		 25 23 48
        one
    		 50 51 101
        two
    		 3 1 4
    Stage
    Measure Description: based on the 7th TNM classification (IASLC classification for SCLC proposal)
    Units: Subjects
        IA
    		 0 2 2
        IB
    		 2 1 3
        IIA
    		 3 5 8
        IIB
    		 6 2 8
        IIIA
    		 26 27 53
        IIIB
    		 40 36 76
        Missing
    		 1 2 3
    Response to chemo-radiotherapy (before randomization)
    Units: Subjects
        Complete response
    		 9 11 20
        Partial response
    		 65 60 125
        Stable disease
    		 4 3 7
        Not evaluable
    		 0 1 1
    Number of radiotherapy fractions per day
    Units: Subjects
        One
    		 48 49 97
        Two
    		 30 26 56
    PEC-CT
    Units: Subjects
        Done
    		 25 26 51
        Not done
    		 53 49 102

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab and Ipilimumab
    Reporting group description
    		 Induction phase: Nivolumab followed (on the same day) by Ipilimumab, for 4 cycles. Maintenance phase: Nivolumab, for a maximum of 12 months from the start of the maintenance phase.

    Reporting group title
    Observation
    Reporting group description
    		 No further treatment after chemo-radiotherapy and PCI.

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Defined as the time from the date of randomisation until documented progression or death, if progression is not documented. Censoring for PFS occurs at the last tumor assessment. Assessment of Progressive Disease (PD) based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Target lesions: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study (this includes the baseline sum if that is the smallest on the study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target lesions: Unequivocal progression of existing non-target lesions. To achieve 'unequivocal progression', there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently. The appearance of one or more new lesions is also considered as progression.
    End point type
    Primary
    End point timeframe
    From the date of randomisation until documented progression or death, assessed up to 4.5 years after the enrolment of the last patient.
    End point values
    		 Nivolumab and Ipilimumab Observation
    Number of subjects analysed
    78 [1]
    75 [2]
    Units: months
        median (confidence interval 95%)
    10.7 (7.0 to 9999)
    14.5 (8.2 to 9999)
    Notes
    [1] - The upper 95% CI is not estimable. Since letters are not accepted, a value of "9999" is entered.
    [2] - The upper 95% CI is not estimable. Since letters are not accepted, a value of "9999" is entered.
    Statistical analysis title
    		 Primary efficacy analysis of PFS
    Statistical analysis description
    The trial is designed to test the hypotheses that treatment with chemoradiotherapy and PCI followed by consolidation treatment (nivolumab plus ipilimumab) will lead to an increase in median PFS to 22.8 months, from 13.1 months under treatment with chemoradiotherapy and PCI without consolidation treatment. According to the study design, this corresponds to a PFS HR of 0.57. Using 80% power and a one-sided type I error of 5%, a total of 81 PFS events are needed.
    Comparison groups
    Observation v Nivolumab and Ipilimumab
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.93 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.58
    Notes
    [3] - In the frame of final efficacy analysis, the formal comparison of the PFS between the two treatment arms, will be based on stratified log-rank test (with number of fractions of radiotherapy [1/2] and administration of FDG-PET-CT [Yes/No] being the stratification factors).
    [4] - The statistical significance of trial treatment will be tested at the 5% significance level.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Defined as the time from the date of randomisation until death from any cause. Censoring for OS occurs at the last follow-up date.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until death from any cause, assessed up to 4.5 years after the enrolment of the last patient.
    End point values
    		 Nivolumab and Ipilimumab Observation
    Number of subjects analysed
    78 [5]
    75 [6]
    Units: months
        median (confidence interval 95%)
    9999 (24.1 to 9999)
    32.1 (26.1 to 9999)
    Notes
    [5] - The median is not reached and the upper 95% CI is not estimable. A value of "9999" is entered.
    [6] - The upper 95% CI is not estimable. Since letters are not accepted, a value of "9999" is entered.
    Statistical analysis title
    		 Secondary efficacy analysis of OS
    Comparison groups
    Nivolumab and Ipilimumab v Observation
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.52
    Notes
    [7] - The statistical significance of trial treatment will be tested at the 5% significance level.

    Secondary: Objective response (OR)

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    End point title
    		 Objective response (OR)
    End point description
    Objective response is defined as the best overall response (complete or partial response) according to RECIST 1.1 criteria across all assessment time-points during the period from randomisation to termination of trial treatment. Of note, the determination of OR is restricted to patients who have not attained a CR during the chemo-radiotherapy phase. Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters, Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm., Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.
    End point type
    Secondary
    End point timeframe
    From randomisation to termination of trial treatment, for a maximum of 12 months from start of maintenance phase.
    End point values
    		 Nivolumab and Ipilimumab Observation
    Number of subjects analysed
    69 [8]
    64 [9]
    Units: subjects
        Complete response
    6
    8
        Partial response
    20
    22
        Stable disease
    28
    22
        Progressive disease
    9
    10
        Non-evaluable
    6
    2
    Notes
    [8] - 9 patients in experimental arm who have attained a CR during chemo-radiotherapy are excluded
    [9] - 11 patients in observation arm who have attained a CR during chemo-radiotherapy are excluded
    No statistical analyses for this end point

    Secondary: Time-to-treatment Failure (TTF)

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    End point title
    		 Time-to-treatment Failure (TTF)
    End point description
    Defined as the time from the date of randomisation to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal, lost to follow-up, and death). Censoring for TTF occurs at the last follow-up date.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until discontinuation of treatment for any reason, assessed up to 4.5 years after the enrolment of the last patient.
    End point values
    		 Nivolumab and Ipilimumab Observation
    Number of subjects analysed
    78
    75
    Units: months
        median (confidence interval 95%)
    1.7 (1.2 to 2.5)
    14.5 (8.2 to 24.0)
    No statistical analyses for this end point

    Secondary: Toxicity

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    End point title
    		 Toxicity
    End point description
    Adverse events graded according to NCI CTCAE V4.0.
    End point type
    Secondary
    End point timeframe
    Toxicity was assessed across all time-points during randomization phase until 100 days after the final dose of investigational medical product (IMP).
    End point values
    		 Nivolumab and Ipilimumab Observation
    Number of subjects analysed
    78 [10]
    75 [11]
    Units: Subjects
        Patients experienced AEs/SAEs
    77
    65
        Patients not experienced AEs/SAEs
    1
    10
        Number of total AEs/SAEs
    633
    242
    Notes
    [10] - Safety cohort
    [11] - Safety cohort
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were assessed across all time-points during randomization phase until 100 days after the final dose of investigational medical product (IMP).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Nivolumab and Ipilimumab
    Reporting group description
    		 Induction phase: Nivolumab followed (on the same day) by Ipilimumab, for 4 cycles. Maintenance phase: Nivolumab, for a maximum of 12 months from the start of the maintenance phase.

    Reporting group title
    Observation
    Reporting group description
    		 No further treatment after chemo-radiotherapy and PCI.

    Serious adverse events
    		 Nivolumab and Ipilimumab Observation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 78 (61.54%)
    12 / 75 (16.00%)
         number of deaths (all causes)
    34
    37
         number of deaths resulting from adverse events
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death NOS
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fever
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    9 / 78 (11.54%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    8 / 22
    0 / 4
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    White blood cell decreased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    8 / 78 (10.26%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    8 / 22
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 19
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    3 / 22
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral meningitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    4 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 25
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Nivolumab and Ipilimumab Observation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 78 (92.31%)
    62 / 75 (82.67%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 75 (1.33%)
         occurrences all number
    6
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 75 (1.33%)
         occurrences all number
    5
    1
    Platelet count decreased
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 75 (6.67%)
         occurrences all number
    4
    5
    Weight loss
         subjects affected / exposed
    7 / 78 (8.97%)
    2 / 75 (2.67%)
         occurrences all number
    7
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 78 (11.54%)
    8 / 75 (10.67%)
         occurrences all number
    9
    8
    Headache
         subjects affected / exposed
    11 / 78 (14.10%)
    2 / 75 (2.67%)
         occurrences all number
    11
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    7 / 78 (8.97%)
    2 / 75 (2.67%)
         occurrences all number
    8
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    7 / 78 (8.97%)
    13 / 75 (17.33%)
         occurrences all number
    7
    13
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 75 (1.33%)
         occurrences all number
    5
    1
    Fatigue
         subjects affected / exposed
    38 / 78 (48.72%)
    21 / 75 (28.00%)
         occurrences all number
    38
    21
    Fever
         subjects affected / exposed
    8 / 78 (10.26%)
    1 / 75 (1.33%)
         occurrences all number
    11
    1
    Pain
         subjects affected / exposed
    9 / 78 (11.54%)
    9 / 75 (12.00%)
         occurrences all number
    9
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 75 (1.33%)
         occurrences all number
    7
    1
    Constipation
         subjects affected / exposed
    14 / 78 (17.95%)
    3 / 75 (4.00%)
         occurrences all number
    15
    3
    Diarrhea
         subjects affected / exposed
    14 / 78 (17.95%)
    6 / 75 (8.00%)
         occurrences all number
    22
    6
    Dry mouth
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 75 (0.00%)
         occurrences all number
    6
    0
    Dysphagia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 75 (2.67%)
         occurrences all number
    4
    2
    Mucositis oral
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 75 (0.00%)
         occurrences all number
    5
    0
    Nausea
         subjects affected / exposed
    18 / 78 (23.08%)
    6 / 75 (8.00%)
         occurrences all number
    19
    6
    Vomiting
         subjects affected / exposed
    20 / 78 (25.64%)
    5 / 75 (6.67%)
         occurrences all number
    21
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 78 (25.64%)
    5 / 75 (6.67%)
         occurrences all number
    20
    5
    Dyspnea
         subjects affected / exposed
    12 / 78 (15.38%)
    5 / 75 (6.67%)
         occurrences all number
    13
    6
    Pneumonitis
         subjects affected / exposed
    13 / 78 (16.67%)
    3 / 75 (4.00%)
         occurrences all number
    22
    4
    Productive cough
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 75 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 75 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    19 / 78 (24.36%)
    0 / 75 (0.00%)
         occurrences all number
    19
    0
    Rash acneiform
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    Rash maculo-papular
         subjects affected / exposed
    10 / 78 (12.82%)
    0 / 75 (0.00%)
         occurrences all number
    10
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 75 (2.67%)
         occurrences all number
    5
    2
    Insomnia
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 75 (1.33%)
         occurrences all number
    5
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    19 / 78 (24.36%)
    0 / 75 (0.00%)
         occurrences all number
    22
    0
    Hypothyroidism
         subjects affected / exposed
    12 / 78 (15.38%)
    0 / 75 (0.00%)
         occurrences all number
    13
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 75 (4.00%)
         occurrences all number
    5
    3
    Back pain
         subjects affected / exposed
    4 / 78 (5.13%)
    7 / 75 (9.33%)
         occurrences all number
    4
    7
    Myalgia
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 75 (1.33%)
         occurrences all number
    5
    1
    Infections and infestations
    Lung infection
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 75 (2.67%)
         occurrences all number
    10
    4
    Upper respiratory infection
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 75 (2.67%)
         occurrences all number
    4
    2
    Urinary tract infection
         subjects affected / exposed
    7 / 78 (8.97%)
    3 / 75 (4.00%)
         occurrences all number
    8
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    23 / 78 (29.49%)
    12 / 75 (16.00%)
         occurrences all number
    25
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2015
    ETOP/IFCT 4-12 STIMULI trial was activated in December 2013 (under original protocol). The low accrual rate experienced in the first few months of the STIMULI study, along with presented results showing significant benefits with Nivolumab treatment with or without Ipilimumab (Antonia S.J. et.al., 2015; Larkin J. et.al., 2015; Postow M.A. et.al, 2017), led the protocol team to decide to proceed to a protocol amendment. The main modifications introduced by the amendment were: • the addition of Nivolumab to consolidation therapy • the addition of carboplatin to standard therapy as an alternative to cisplatin • the addition of PFS as co-primary endpoint • the option of contrast enhanced CT of the brain as an alternative to MRI at screening • allowing one cycle of chemotherapy before enrolment of a patient.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Apr 2019
    Because of the low accrual rate of STIMULI trial, as well as additional internal strategic considerations unrelated to the scientific rational or trial design, BMS decided not to continue funding the STIMULI trial. Thus, the trial Steering Committee decided to close the accrual of the trial permanently as of April 30, 2019. Patients who had already consented were still allowed to be enrolled until April 30, 2019. After this date, no new patients were allowed to be enrolled into the trial. Treatment and follow-up for all included patients continued as per protocol. Patients in the chemo-radiotherapy phase who met the criteria were still allowed to be randomised.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    After premature accrual closure, the statistical design was modified and the primary endpoint of the trial was finally defined as only the PFS (previous: co-primary PFS and OS).
    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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