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    Clinical Trial Results:
    REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer

    Summary
    EudraCT number
    		 2014-003090-42
    Trial protocol
    		 GB   IT  
    Global end of trial date
    22 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2024
    First version publication date
    17 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1417-LCG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02580994
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Clinical Operations Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 2 774 15 11, regulatory@eortc.be
    Scientific contact
    Clinical Operations Department, European Organisation for Research and Treatment of Cancer (EORTC), +32 2 774 15 11, regulatory@eortc.be
    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
    10 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main aim of this study is to evaluate the activity measured by progression free survival (PFS) of pembrolizumab in combination with etoposide and cis/carboplatin followed by pembrolizumab alone (continuation maintenance) versus etoposide and cis/carboplatin alone in chemo-sensitive patients with ED-SCLC.
    Protection of trial subjects
    The responsible investigator will ensure that this study is 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 has been written, and the study will be conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-practice_en.pdf). The protocol must be approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 Combination chemotherapies are the current standard of care for ED-SCLC. The chemotherapy agents commonly available for the treatment of SCLC include cyclophosphamide, doxorubicin, methotrexate, etoposide, vincristine, cisplatin and carboplatin. In this trial, the control arm will involve treatment with a combination of etoposide and carboplatin or cisplatin
    Evidence for comparator
    		 Cisplatin and carboplatin as combination partners for etoposide display a similar efficacy profile in terms of OS, PFS, or ORR (median OS: 9.6 versus 9.4 months; median PFS: 5.5 versus 5.3 months; and ORR: 67 versus 66%, respectively) for patient with Extensive-disease SLCL (Rossi A, Di Maio M, Chiodini P et al. J Clin Oncol 2012).
    Actual start date of recruitment
    07 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    France: 93
    Country: Number of subjects enrolled
    Italy: 23
    Worldwide total number of subjects
    125
    EEA total number of subjects
    116
    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)
    64
    From 65 to 84 years
    61
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 07/02/2018 and 31/10/2019, 125 patients with ED-SCLC, unselected for PD-L1, having an objective response after 2 cycles of platinum-etoposide, with PS 0/1 and controlled brain metastases at the time of tumor evaluation were randomized in 3 countries (France, Italy, United Kingdom).

    Pre-assignment
    Screening details
    		 Patients' enrollment followed a two-step process. Upon signing the informed consent, patients were registered and a sample of the tumor, if available, was sent for PD-L1 expression assessment (registration step). After two cycles of chemotherapy, the patient was reassessed to verify eligibility for the randomization (randomization step).

    Pre-assignment period milestones
    Number of subjects started
    		 169 [1]
    Number of subjects completed
    		 125

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 No response after induction chemotherapy: 19
    Reason: Number of subjects
    		 Patients died before randomization: 9
    Reason: Number of subjects
    		 Clinical progression without radiological evidence: 2
    Reason: Number of subjects
    		 Patient ineligible for another reason: 10
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients who entered the pre-assignment period and are not randomized are screen failures. Reasons for screening failures were provided.
    Period 1
    Period 1 title
    From randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard arm
    Arm description
    		 4 cycles of cisplatin/carboplatin and etoposide (after the 2 cycles before randomization) A maximum of 4 cycles of chemotherapy (after randomization) will be administered (6 cycles overall) unless there is tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s). Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 80 mg/m2 on day 1 (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 5 IV infusion on day 1 [the dose of carboplatin will be determined for each cycle using the Calvert’s formula (carboplatin dose (mg) = target AUC 5 x estimated glomerular filtration rate (eGFR, mL/min) + 25)] (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m2 IV infusion on day 1, 2 and 3 (3-weekly cycles for 4 cycles)

    Arm title
    		 Experimental arm
    Arm description
    		 Pembrolizumab (MK-3475) in combination with cisplatin/carboplatin and etoposide for 4 cycles (after the 2 cycles before randomization) and pembrolizumab (MK-3475) to be continued alone as maintenance until a total of 35 cycles, progressive disease (PD) or death. Dosing cycles of pembrolizumab will continue until administration of a total of 35 cycles, tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s) occurs. If at the time of disease progression, the patient still has a major clinical benefit, the patient is allowed to continue receiving the treatment if the investigator thinks this is in the best interest of the patient up to a total of 35 cycles of pembrolizumab. Rechallenge with pembrolizumab alone is allowed with a maximum of 17 cycles of pembrolizumab after disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 80 mg/m2 on day 1 (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 5 IV infusion on day 1 [the dose of carboplatin will be determined for each cycle using the Calvert’s formula (carboplatin dose (mg) = target AUC 5 x estimated glomerular filtration rate (eGFR, mL/min) + 25)] (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m2 IV infusion on day 1, 2 and 3 (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab (MK-3475) will be administered via IV infusion at the dose of 200 mg on day 1 (30 minutes: -5/+10 min) every three weeks

    Number of subjects in period 1
    		Standard arm Experimental arm
    Started
    64
    61
    Completed
    56
    44
    Not completed
    8
    17
         Adverse event, serious fatal
    1
    1
         On treatment or end of treatment form not received
    1
    8
         Adverse event, non-fatal
    4
    8
         Death not due to malignant disease or AE
    1
    -
         Missing reason
    1
    -
    Period 2
    Period 2 title
    Cross-over to pembrolizumab
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Standard arm
    Arm description
    		 Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm. Patients assigned to the standard arm who experience disease progression at least 3 months after the last dose of chemotherapy treatment and meet all crossover criteria, will have the opportunity to crossover to cisplatin/carboplatin and etoposide and pembrolizumab every three weeks for a maximum of 6 cycles followed by pembrolizumab alone every three weeks until 35 cycles are administered or disease progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 80 mg/m2 on day 1 (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 5 IV infusion on day 1 [the dose of carboplatin will be determined for each cycle using the Calvert’s formula (carboplatin dose (mg) = target AUC 5 x estimated glomerular filtration rate (eGFR, mL/min) + 25)] (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m2 IV infusion on day 1, 2 and 3 (3-weekly cycles for 4 cycles)

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    MK-3475
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab (MK-3475) will be administered via IV infusion at the dose of 200 mg on day 1 (30 minutes: -5/+10 min) every three weeks

    Number of subjects in period 2 [2]
    		Standard arm
    Started
    19
    Completed
    14
    Not completed
    5
         Adverse event, serious fatal
    1
         On treatment or treatment form not received
    3
         Adverse event, non-fatal
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Cross-over was allowed at the time of progressive disease according to RECIST 1.1 in the standard arm. Cross-over was therefore only applicable to the standard arm and to patients experiencing progressive disease.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard arm
    Reporting group description
    		 4 cycles of cisplatin/carboplatin and etoposide (after the 2 cycles before randomization) A maximum of 4 cycles of chemotherapy (after randomization) will be administered (6 cycles overall) unless there is tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s). Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm.

    Reporting group title
    Experimental arm
    Reporting group description
    		 Pembrolizumab (MK-3475) in combination with cisplatin/carboplatin and etoposide for 4 cycles (after the 2 cycles before randomization) and pembrolizumab (MK-3475) to be continued alone as maintenance until a total of 35 cycles, progressive disease (PD) or death. Dosing cycles of pembrolizumab will continue until administration of a total of 35 cycles, tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s) occurs. If at the time of disease progression, the patient still has a major clinical benefit, the patient is allowed to continue receiving the treatment if the investigator thinks this is in the best interest of the patient up to a total of 35 cycles of pembrolizumab. Rechallenge with pembrolizumab alone is allowed with a maximum of 17 cycles of pembrolizumab after disease progression.

    Reporting group values
    		 Standard arm Experimental arm Total
    Number of subjects
    		 64 61 125
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 63.5 (58 to 68.5) 65 (60 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 28 17 45
        Male
    		 36 44 80
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 24 18 42
        ECOG 1
    		 37 41 78
        ECOG 2
    		 2 2 4
        ECOG 3
    		 1 0 1
    Cigarette usage
    Units: Subjects
        Never
    		 3 0 3
        Current
    		 21 22 43
        Former
    		 40 39 79
    Known CNS metastases (before induction chemotherapy)
    Units: Subjects
        No
    		 57 56 113
        Yes, stable
    		 7 5 12
    Induction chemotherapy
    Units: Subjects
        Cisplatin/etoposide
    		 19 18 37
        Carboplatin/etoposide
    		 45 43 88
    Response to induction
    Units: Subjects
        Complete response (CR)
    		 1 1 2
        Partial response (PR)
    		 63 60 123

    End points

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    End points reporting groups
    Reporting group title
    Standard arm
    Reporting group description
    		 4 cycles of cisplatin/carboplatin and etoposide (after the 2 cycles before randomization) A maximum of 4 cycles of chemotherapy (after randomization) will be administered (6 cycles overall) unless there is tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s). Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm.

    Reporting group title
    Experimental arm
    Reporting group description
    		 Pembrolizumab (MK-3475) in combination with cisplatin/carboplatin and etoposide for 4 cycles (after the 2 cycles before randomization) and pembrolizumab (MK-3475) to be continued alone as maintenance until a total of 35 cycles, progressive disease (PD) or death. Dosing cycles of pembrolizumab will continue until administration of a total of 35 cycles, tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s) occurs. If at the time of disease progression, the patient still has a major clinical benefit, the patient is allowed to continue receiving the treatment if the investigator thinks this is in the best interest of the patient up to a total of 35 cycles of pembrolizumab. Rechallenge with pembrolizumab alone is allowed with a maximum of 17 cycles of pembrolizumab after disease progression.
    Reporting group title
    Standard arm
    Reporting group description
    		 Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm. Patients assigned to the standard arm who experience disease progression at least 3 months after the last dose of chemotherapy treatment and meet all crossover criteria, will have the opportunity to crossover to cisplatin/carboplatin and etoposide and pembrolizumab every three weeks for a maximum of 6 cycles followed by pembrolizumab alone every three weeks until 35 cycles are administered or disease progression.

    Subject analysis set title
    Per protocol population - standard arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who are eligible and have started their allocated treatment (at least one dose of the study drug(s)). Note: The primary analyses of the primary and secondary endpoints will be performed on the per-protocol population. A sensitivity analysis of efficacy based on intent to treat (ITT) population was conducted for PFS and OS in addition to the primary analysis based on per protocol population.

    Subject analysis set title
    Per protocol population - experimental arm
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who are eligible and have started their allocated treatment (at least one dose of the study drug(s)). Note: The primary analyses of the primary and secondary endpoints will be performed on the per-protocol population. A sensitivity analysis of efficacy based on intent to treat (ITT) population was conducted for PFS and OS in addition to the primary analysis based on per protocol population.

    Subject analysis set title
    Per protocol population - cross-over
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who are eligible and have started their allocated treatment (at least one dose of the study drug(s)).

    Primary: Progression free survival according to RECIST 1.1

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    End point title
    		 Progression free survival according to RECIST 1.1
    End point description
    Progression Free Survival (PFS) is defined as the time interval between the date of randomization and the date of disease progression according to RECIST 1.1 or death, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow up examination.
    End point type
    Primary
    End point timeframe
    Disease evaluation will be performed every six weeks during treatment period and every 3 months during follow up until PD/death whichever occurs first.
    End point values
    		 Standard arm Experimental arm Per protocol population - standard arm Per protocol population - experimental arm
    Number of subjects analysed
    64
    61
    61
    58
    Units: Months
        median (confidence interval 95%)
    5.4 (4.7 to 5.5)
    4.6 (4.2 to 5.5)
    5.4 (4.7 to 5.6)
    4.7 (4.2 to 5.6)
    Attachments
    		 Progression free survival - per protocol
    Statistical analysis title
    		 Primary analysis adjusted (per protocol)
    Statistical analysis description
    The primary analysis of PFS was performed on the per protocol population. Cox regression (Wald Test) was used to compare the experimental versus the control arms adjusted by the stratification factors in randomization (except for centers) at 1-sided 10% significant level.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1941 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.09
    Notes
    [1] - The one-sided p-value for the primary test of a difference in PFS in favor of the experimental arm is 0.1941, not significant at 1-sided 10% significant level.
    Statistical analysis title
    		 Sensitivity analysis adjusted (ITT)
    Statistical analysis description
    A sensitivity analysis of PFS based on the intent to treat (ITT) population will be conducted in addition to the primary analysis based on the per protocol population.
    Comparison groups
    Standard arm v Experimental arm
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2304 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.11
    Notes
    [2] - The one-sided p-value for the primary test of a difference in PFS in favor of the experimental arm is 0.2304, not significant at 1-sided 10% significant level.

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall Survival (OS) is defined as the time interval between the date of randomization and the date of death from any cause. If no event has been observed, then the patient is censored at the last date known to be alive.
    End point type
    Secondary
    End point timeframe
    After the end of treatment, patients will be followed for survival (all arms). Follow-up visits to the hospital and frequency of tumor evaluation will be performed every three months.
    End point values
    		 Standard arm Experimental arm Per protocol population - standard arm Per protocol population - experimental arm
    Number of subjects analysed
    64
    61
    61
    58
    Units: Months
        median (confidence interval 95%)
    11.1 (8.3 to 14.4)
    12.3 (8.9 to 14.8)
    10.4 (8.2 to 12.2)
    12.3 (8.9 to 14.8)
    Attachments
    		 Overall survival - per protocol
    Statistical analysis title
    		 Primary analysis adjusted (per protocol)
    Statistical analysis description
    The primary analysis of OS was performed on the per protocol population. Cox regression (Wald Test) was used to compare the experimental versus the control arms adjusted by the stratification factors in randomization (except for centers) at 1-sided 10% significant level.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0971 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1
    Notes
    [3] - The one-sided p-value for the test of a difference in OS in favor of the experimental arm is 0.0971.
    Statistical analysis title
    		 Sensitivity analysis adjusted (ITT)
    Statistical analysis description
    A sensitivity analysis of OS based on the intent to treat (ITT) population will be conducted in addition to the primary analysis based on the per protocol population.
    Comparison groups
    Standard arm v Experimental arm
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1958 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.1
    Notes
    [4] - The one-sided p-value for the test of a difference in OS in favor of the experimental arm is 0.1958.

    Secondary: Response according to RECIST 1.1

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    End point title
    		 Response according to RECIST 1.1
    End point description
    All patients will have their BEST OVERALL RESPONSE (BOR) evaluated according to the RECIST 1.1 criteria from the start of treatment until the end of treatment and classified as complete response (CR) or partial response (PR) or stable disease (SD) or progressive disease (PD) or not evaluable or early death according to RECIST 1.1 criteria. Response is CR or PR.
    End point type
    Secondary
    End point timeframe
    Disease evaluation will be performed every six weeks during the treatment period.
    End point values
    		 Per protocol population - standard arm Per protocol population - experimental arm Per protocol population - cross-over
    Number of subjects analysed
    61
    58
    17
    Units: Subject
        Complete response (CR)
    2
    3
    1
        Partial response (PR)
    32
    36
    6
        Stable disease (SD)
    22
    15
    6
        Progressive disease (PD)
    3
    3
    4
        Inevaluable
    1
    1
    0
        Early death
    1
    0
    0
    Statistical analysis title
    		 Primary analysis - comparative
    Statistical analysis description
    The analysis of response rate according to RECIST 1.1 will be performed on the per-protocol population.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.1977
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.115
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0585
         upper limit
    		 0.2886
    Notes
    [5] - The response rates in each arm and their 95% confidence intervals will be provided. In addition, response rates in the 2 arms will be compared using a two-sample test at 5% 2-sided level.
    Statistical analysis title
    		 Descriptive analysis - standard arm
    Statistical analysis description
    The response rates in each arm and their two-sided 95% confidence intervals will be provided.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm v Per protocol population - cross-over
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Proportion
    Point estimate
    55.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 42.4
         upper limit
    		 68.5
    Notes
    [6] - This is not a formal comparative analysis between the two arms but a descriptive analysis in each arm and in the standard arm for the cross-over treatment.
    Statistical analysis title
    		 Descriptive analysis - experimental arm
    Statistical analysis description
    The response rates in each arm and their two-sided 95% confidence intervals will be provided.
    Comparison groups
    Per protocol population - experimental arm v Per protocol population - standard arm v Per protocol population - cross-over
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Proportion
    Point estimate
    67.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.7
         upper limit
    		 79
    Notes
    [7] - This is not a formal comparative analysis between the two arms but a descriptive analysis in each arm and in the standard arm for the cross-over treatment.
    Statistical analysis title
    		 Descriptive analysis - cross-over
    Statistical analysis description
    The response rates to the cross-over treatment and their 95% confidence intervals will be provided.
    Comparison groups
    Per protocol population - cross-over v Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Proportion
    Point estimate
    41.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.4
         upper limit
    		 67.1
    Notes
    [8] - This is not a formal comparative analysis between the two arms but a descriptive analysis in each arm and in the standard arm for the cross-over treatment.

    Secondary: Disease control according to RECIST 1.1

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    End point title
    		 Disease control according to RECIST 1.1
    End point description
    All patients will have their BEST OVERALL RESPONSE (BOR) evaluated according to the RECIST 1.1 criteria from the start of treatment until the end of treatment. Disease control is achieved when BOR is complete response (CR) or partial response (PR) or stable disease (SD).
    End point type
    Secondary
    End point timeframe
    Disease evaluation will be performed every six weeks during the treatment period.
    End point values
    		 Per protocol population - standard arm Per protocol population - experimental arm
    Number of subjects analysed
    61
    58
    Units: Subject
        Yes
    56
    54
        No
    5
    4
    Statistical analysis title
    		 Descriptive analysis - standard arm
    Statistical analysis description
    The disease control rates in each arm and their two-sided 95% confidence intervals will be provided.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Proportion
    Point estimate
    91.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 81.9
         upper limit
    		 97.3
    Notes
    [9] - This is not a formal comparative analysis between the two arms but a descriptive analysis in each arm.
    Statistical analysis title
    		 Descriptive analysis - experimental arm
    Statistical analysis description
    The disease control rates in each arm and their two-sided 95% confidence intervals will be provided.
    Comparison groups
    Per protocol population - experimental arm v Per protocol population - standard arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Proportion
    Point estimate
    93.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 83.3
         upper limit
    		 98.1
    Notes
    [10] - This is not a formal comparative analysis between the two arms but a descriptive analysis in each arm.

    Secondary: Progression free survival according to RECIST 1.1 after cross-over

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    End point title
    		 Progression free survival according to RECIST 1.1 after cross-over
    End point description
    Progression free survival (PFS) after cross-over is defined as the time interval between the start of the cross-over treatment and the date of disease progression according to RECIST 1.1 or death, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow up examination.
    End point type
    Secondary
    End point timeframe
    Disease evaluation will be performed every six weeks during cross-over treatment period and every 3 months during follow up until PD/death whichever occurs first.
    End point values
    		 Per protocol population - cross-over
    Number of subjects analysed
    17
    Units: Months
        median (confidence interval 95%)
    6.7 (3.1 to 9.7)
    No statistical analyses for this end point

    Secondary: Progression free survival at second progression (PFS-2)

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    End point title
    		 Progression free survival at second progression (PFS-2)
    End point description
    PFS-2 is calculated as the time between randomization and the PD or death, not of the current treatment but the PD after the subsequent treatment thus taking into account the influence of the treatment under investigation on the following treatment line. Details on the events for PFS-2 are given Table 1 (see uploaded attachment).
    End point type
    Secondary
    End point timeframe
    Disease evaluation will be performed every six weeks during treatment period and every 3 months during follow up until PD/death whichever occurs first.
    End point values
    		 Per protocol population - standard arm Per protocol population - experimental arm
    Number of subjects analysed
    61
    58
    Units: Months
        median (confidence interval 95%)
    9.0 (7.9 to 10.3)
    10.3 (7.8 to 13.7)
    Attachments
    		 Table 1. Events for PFS-2
    PFS-2 per protocol
    Statistical analysis title
    		 Primary analysis adjusted (per protocol)
    Statistical analysis description
    The primary analysis of PFS-2 was performed on the per protocol population. Cox regression (Wald Test) was used to compare the experimental versus the control arms adjusted by the stratification factors in randomization (except for centers) at 1-sided 10% significant level.
    Comparison groups
    Per protocol population - standard arm v Per protocol population - experimental arm
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0124 [11]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.8
    Notes
    [11] - The one-sided p-value for the primary test of a difference in PFS in favor of the experimental arm is 0.0124, significant at 1-sided 10% significant level.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from the randomization till the end of treatment (within 30 days after treatment discontinuation).
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs have 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
    Experimental arm
    Reporting group description
    		 Pembrolizumab (MK-3475) in combination with cisplatin/carboplatin and etoposide for 4 cycles (after the 2 cycles before randomization) and pembrolizumab (MK-3475) to be continued alone as maintenance until a total of 35 cycles, progressive disease (PD) or death. Dosing cycles of pembrolizumab will continue until administration of a total of 35 cycles, tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s) occurs. If at the time of disease progression, the patient still has a major clinical benefit, the patient is allowed to continue receiving the treatment if the investigator thinks this is in the best interest of the patient up to a total of 35 cycles of pembrolizumab. Rechallenge with pembrolizumab alone is allowed with a maximum of 17 cycles of pembrolizumab after disease progression.

    Reporting group title
    Standard arm
    Reporting group description
    		 4 cycles of cisplatin/carboplatin and etoposide (after the 2 cycles before randomization) A maximum of 4 cycles of chemotherapy (after randomization) will be administered (6 cycles overall) unless there is tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator or his/her designated associate(s). Cross-over at the time of progressive disease according to RECIST 1.1 is allowed for the standard arm.

    Serious adverse events
    		 Experimental arm Standard arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 60 (35.00%)
    20 / 64 (31.25%)
         number of deaths (all causes)
    27
    23
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASM PROGRESSION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARANEOPLASTIC SYNDROME
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    VENOUS THROMBOSIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PYREXIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    INTERSTITIAL LUNG DISEASE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FLUTTER
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ATRIAL FIBRILLATION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIAC FAILURE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MYOCARDITIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GUILLAIN-BARRE SYNDROME
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    SYNCOPE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOLYTIC ANAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE-MEDIATED ENTEROCOLITIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL TUBULAR NECROSIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOTHYROIDISM
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADRENAL INSUFFICIENCY
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    LOWER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    UPPER RESPIRATORY TRACT INFECTION
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    HYPONATRAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
    alternative dictionary used: MedDRA 24.1
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Experimental arm Standard arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 60 (98.33%)
    60 / 64 (93.75%)
    Vascular disorders
    HEMATOMA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    HYPERTENSION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    9 / 64 (14.06%)
         occurrences all number
    1
    14
    PHLEBITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SUPERFICIAL THROMBOPHLEBITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    THROMBOEMBOLIC EVENT
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    8 / 60 (13.33%)
    1 / 64 (1.56%)
         occurrences all number
    9
    1
    General disorders and administration site conditions
    ALOPECIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    FEVER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    8 / 60 (13.33%)
    1 / 64 (1.56%)
         occurrences all number
    9
    1
    FATIGUE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    23 / 60 (38.33%)
    23 / 64 (35.94%)
         occurrences all number
    36
    39
    EDEMA LIMBS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    EDEMA FACE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    CHILLS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    ALTERATION OF GENERAL CONDITION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    HEADACHE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    GENERAL DISORDERS ANDADMINISTRATION SITE CONDITIONS -OTHER, DETERIORATION OF THE GENERAL CONDITION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, DETERIORATION OF HEALTH STATUS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, ALTERATION OF GENERAL CONDITION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    GAIT DISTURBANCE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    MALAISE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    FLU LIKE SYMPTOMS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    NON-CARDIAC CHEST PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 64 (4.69%)
         occurrences all number
    5
    3
    PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    Immune system disorders
    ALLERGIC REACTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    4
    Reproductive system and breast disorders
    REPRODUCTIVE SYSTEM AND BREAST DISORDERS - OTHER, PENIS INFLAMMATION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    REPRODUCTIVE SYSTEM AND BREAST DISORDERS - OTHER, BLEEDING FROM FORESKIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    DYSPNEA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    13 / 60 (21.67%)
    14 / 64 (21.88%)
         occurrences all number
    16
    14
    COUGH
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 64 (7.81%)
         occurrences all number
    10
    5
    BRONCHIAL OBSTRUCTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    ALLERGIC RHINITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    PULMONARY EDEMA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    PNEUMONITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    NASAL CONGESTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    LARYNGEAL HEMORRHAGE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    HOARSENESS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    EPISTAXIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    PULMONARY FIBROSIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    RESPIRATORY OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    RESPIRATORY FAILURE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    WORSENING OF RESPIRATORY FAILURE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    VOICE ALTERATION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SORE THROAT
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDER - OTHER, LUNG BOOP SYNDROM
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    INSOMNIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    CONFUSION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    ANXIETY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
         occurrences all number
    8
    2
    CD4 LYMPHOCYTES DECREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    7
    1
    LYMPHOCYTE COUNT DECREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    INVESTIGATIONS - OTHER, LACTATE DEHYDROGENASE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    GGT INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    7 / 60 (11.67%)
    5 / 64 (7.81%)
         occurrences all number
    12
    7
    ELECTROCARDIOGRAM QT CORRECTED INTERVAL PROLONGED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    CREATININE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 64 (3.13%)
         occurrences all number
    13
    2
    ALKALINE PHOSPHATASE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    2
    NEUTROPHIL COUNT DECREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    11 / 60 (18.33%)
    13 / 64 (20.31%)
         occurrences all number
    22
    20
    WHITE BLOOD CELL DECREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    WHITE BLOOD CELL DECREASE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    WEIGHT LOSS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 64 (4.69%)
         occurrences all number
    5
    3
    WEIGHT GAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    PLATELET COUNT DECREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    17 / 60 (28.33%)
    18 / 64 (28.13%)
         occurrences all number
    22
    38
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    FALL
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Cardiac disorders
    CARDIAC ARREST
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    CHEST PAIN - CARDIAC
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    HEART FAILURE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    ATRIAL FLUTTER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    ATRIAL FIBRILLATION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    MYOCARDITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    MYOCARDIAL INFARCTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    PALPITATIONS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SUPRAVENTRICULAR TACHYCARDIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SINUS TACHYCARDIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
         occurrences all number
    3
    3
    SINUS BRADYCARDIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    THROMBOEMBOLIC EVENT
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    VENTRICULAR ARRHYTHMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    ACOUSTIC NERVE DISORDER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    ATAXIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    DEPRESSED LEVEL OF CONSCIOUSNESS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    DIZZINESS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    DYSGEUSIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
         occurrences all number
    5
    2
    HEADACHE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    MYELITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
         occurrences all number
    2
    7
    PARESTHESIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 64 (7.81%)
         occurrences all number
    4
    6
    PERIPHERAL MOTOR NEUROPATHY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    PERIPHERAL SENSORY NEUROPATHY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
         occurrences all number
    1
    2
    SEIZURE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    TREMOR
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    TRANSIENT ISCHEMIC ATTACKS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SYNCOPE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    STROKE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    ANEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    30 / 60 (50.00%)
    24 / 64 (37.50%)
         occurrences all number
    76
    48
    FEBRILE NEUTROPENIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    HEARING IMPAIRED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 64 (6.25%)
         occurrences all number
    1
    5
    VERTIGO
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    TINNITUS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Eye disorders
    PHOTOPHOBIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    DRY EYE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    CONJUNCTIVITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    BLURRED VISION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    RETINAL DETACHMENT
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    DYSPEPSIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
         occurrences all number
    1
    3
    DRY MOUTH
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    DIARRHEA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    10 / 60 (16.67%)
    4 / 64 (6.25%)
         occurrences all number
    14
    7
    CONSTIPATION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    9 / 60 (15.00%)
    7 / 64 (10.94%)
         occurrences all number
    9
    8
    COLITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    ABDOMINAL PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    DYSPHAGIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 64 (3.13%)
         occurrences all number
    4
    3
    TOOTHACHE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    NAUSEA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    17 / 60 (28.33%)
    13 / 64 (20.31%)
         occurrences all number
    27
    26
    MUCOSITIS ORAL
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    2
    HEMORRHOIDS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    GASTROESOPHAGEAL REFLUX DISEASE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
         occurrences all number
    1
    3
    ESOPHAGEAL PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    VOMITING
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
         occurrences all number
    5
    3
    Hepatobiliary disorders
    BILE DUCT STENOSIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    HEPATIC FAILURE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    6 / 64 (9.38%)
         occurrences all number
    2
    6
    RASH MACULO-PAPULAR
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, FOLLICULITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, GENITAL CUTANEOUS LESIONS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    RASH ACNEIFORM
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 64 (1.56%)
         occurrences all number
    6
    1
    PRURITUS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 64 (3.13%)
         occurrences all number
    7
    3
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    ERYTHRODERMA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    DRY SKIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 64 (6.25%)
         occurrences all number
    5
    4
    Renal and urinary disorders
    RENAL AND URINARY DISORDERS - OTHER, ACUTE TUBULAR NECROSIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    RENAL AND URINARY DISORDERS - OTHER, POLYURO-POLYDIPSIC SYNDROME
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    CYSTITIS NONINFECTIVE
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    CREATININE INCREASED
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    ACUTE KIDNEY INJURY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    URINARY TRACT PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Endocrine disorders
    ADRENAL INSUFFICIENCY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    HYPERTHYROIDISM
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    8 / 60 (13.33%)
    3 / 64 (4.69%)
         occurrences all number
    8
    5
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    HYPOTHYROIDISM
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 64 (1.56%)
         occurrences all number
    6
    1
    Musculoskeletal and connective tissue disorders
    BONE PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    BACK PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
         occurrences all number
    1
    4
    ARTHRALGIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    NECK PAIN
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    PAIN IN EXTREMITY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    MYALGIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    2
    MUSCLE WEAKNESS UPPER LIMB
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    Infections and infestations
    BLADDER INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    BRONCHIAL INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    PHARYNGITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    PAPULOPUSTULAR RASH
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    NAIL INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    LUNG INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
         occurrences all number
    4
    4
    KIDNEY INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    ESOPHAGEAL INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    PYELONEPHRITIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    VULVAL INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    URINARY TRACT INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    UPPER RESPIRATORY INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 64 (4.69%)
         occurrences all number
    2
    3
    TOOTH INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    SKIN INFECTION
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    SEPSIS
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    ANOREXIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    9 / 60 (15.00%)
    7 / 64 (10.94%)
         occurrences all number
    9
    9
    HYPERKALEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 64 (0.00%)
         occurrences all number
    7
    0
    HYPERGLYCEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 64 (4.69%)
         occurrences all number
    3
    6
    HYPERCALCEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    HYPERURICEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences all number
    5
    0
    HYPONATREMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 64 (3.13%)
         occurrences all number
    3
    6
    HYPOMAGNESEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
         occurrences all number
    5
    3
    HYPOKALEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 64 (6.25%)
         occurrences all number
    1
    6
    HYPOGLYCEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    HYPOCALCEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 64 (4.69%)
         occurrences all number
    6
    3
    OTHER
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    METABOLISM AND NUTRITION DISORDERS - OTHER: VITAMIN B9 DEFICIENCY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    METABOLISM AND NUTRITION DISORDERS - OTHER, DIABETIC NEPHROPATHY
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    HYPOPHOSPHATEMIA
    alternative dictionary used: CTC 4.0
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2016
    SCIENTIFIC AMENDMENT 1 1) In order to clarify the language and align with Merck standard language some eligibility criteria have been rephrased. 2) According to the last version of the IB for Pembrolizumab (v12) the safety language has been updated. 3) After review with Study Coordinators and Statistician, activity of pembrolizumab in combination with carboplatin and etoposide in case of cross over in the control arm and Activity of pembrolizumab alone in case of re-challenge in the experimental arm have been moved from Exploratory to Secondary objectives. 4) To be consistent with other sections some eligibility criteria has been moved from section on Eligibility check to section on Randomization check 7) The protocol has been updated with the correct type and amount of samples for TR projects. The laboratories in charge of the storage and analysis have been added.
    30 Mar 2017
    SCIENTIFIC AMENDMENT 2 Following the routine update of the safety language for Pembrolizumab (IBv13) the protocol and PISIC have been amended and some other clarifications have been added about the Translational research.
    18 Dec 2017
    SCIENTIFIC AMENDMENT 3 -Treatment duration with pembrolizumab alone has been changed to 2 years in order to be consistent with the current protocol. -Risk language was updated according to the IB v14 and v15. -Addition of wording to cover the transfer of data to the US (i.e. MediData).
    23 May 2018
    SCIENTIFIC AMENDMENT 4 Following the requirements from the UK MHRA, the protocol was amendment: - Adequate methods of birth control were added; - Cross-over and re-challenge criteria were added; - The three days window and +/- 10% deviation from reference laboratory values were removed; - Temperature was added to the list of vital signs.
    14 Dec 2018
    SCIENTIFIC AMENDMENT 5 Based on the evidence of a discrepancy in the definition of crossover, the following changes were implemented to the protocol: - Crossover will be allowed for patients randomized in arm B who completed the chemotherapy treatment and progress at least 3 months after the completion of chemotherapy. - A close safety monitoring has been added to be performed on the first 5 patients and then 10 patients in arm B who crossover. In case of safety concern, the study will be presented to the IDMC. - The protocol has been adapted in order to provide information on the examination to be performed as follow-up for those patients who completed treatment and are waiting for crossover or rechallenge and also to provide information on the examination to be performed before re-challenge or crossover and during the re-challenge or crossover treatment period. - The end of treatment has been better defined. Additional changes include: - Primary objective and primary and secondary endpoints have been updated in order to refer to RECIST criteria v1.1 - “Assessment of adequate tissue availability for PD-L1 immunohistochemistry testing” has been removed from the eligibility criteria, as tumor tissue collection is not mandatory for enrolment. - Contraception period required has been adapted in order to be consistent with the SmPCs of chemotherapy drugs and the pregnancy reporting has been adapted accordingly. - For evaluation of eGFR, Cockroft-Gault Formula has been replaced by MDRD formula in the eligibility criteria. - The split of cisplatin administration in 2 days has been added as allowed. - In the withdrawal criteria has been added: “Disease progression according RECIST v1" (Exception: patients who are qualified for re-challenge and crossover)”. -The collection of creatinine clearance during the study treatment has been added. -Recommendation for the pregnancy test has been added. The PISIC has been updated accordingly.
    05 Jul 2019
    SCIENTIFIC AMENDMENT 6 Based on Italian competent authory (AIFA) comment, the following change is added to the protocol: Recurrent G3 colitis has been added as a reason of treatment discontinuation.
    13 May 2020
    SCIENTIFIC AMENDMENT 7 A new appendix to protocol and an addendum to patient information sheet have been prepared to include recommendations related to treatment and evaluations only applicable during the COVID-19 pandemic.
    16 Dec 2020
    SCIENTIFIC AMENDMENT 8 There was a change in the central laboratory which will analyze the tissue samples for TR purpose. Centre Léon Bérard (France) was replaced by the Targos (Kassel, Germany). In addition to the above, the following changes/clarifications have been added: - Appendix was added to provide guidance on protocol procedures during the COVID-19 crisis (COVID-19 appendix and PISIC addendum already released on 13/May/2020) - PISIC has been updated to include the change in the central lab and to include the updated safety language for permbolizumab.

    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
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