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    Clinical Trial Results:
    A Single-Arm, Phase 2 Trial of Pemetrexed, Cisplatin,and Bevacizumab as Induction, Followed by Pemetrexed and Bevacizumab as Maintenance, in First-Line Treatment of Nonsquamous Advanced NSCLC

    Summary
    EudraCT number
    		 2008-006732-35
    Trial protocol
    		 DE   IT   DK   ES   SE  
    Global end of trial date
    06 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2016
    First version publication date
    02 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H3E-EW-S125
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01004250
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial ID: 13034, Trial Alias: H3E-EW-S125
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-CTLILLY,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    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
    06 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Participants with advanced non-small cell lung cancer (NSCLC) will receive a first-line treatment of Pemetrexed, Cisplatin and Bevacizumab as induction therapy followed by a maintenance treatment of Pemetrexed and Bevacizumab. Treatment will continue until disease progression or unacceptable toxicity occurs. The primary objective of this study is to measure how long this treatment could prevent the disease progression.
    Protection of trial subjects
    This study was conducted in accordance with International Code of Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Sweden: 18
    Worldwide total number of subjects
    109
    EEA total number of subjects
    109
    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)
    75
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study had 3 periods: a baseline period; a study treatment period, including both induction (Ind) and maintenance (Maint) treatment; and a follow-up period.

    Period 1
    Period 1 title
    Induction Therapy Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Study Treatment Induction
    Arm description
    		 Induction Therapy: Bevacizumab: 7.5 milligram per kilogram (mg/kg) given intravenously on Day 1 for four cycles (cycle=21 days) of Induction Therapy. Pemetrexed: 500 milligram per square meter (mg/m²) given intravenously on Day 1 for four cycles of Induction Therapy. Cisplatin: 75 mg/m² given intravenously on Day 1 for a maximum of 4 cycles. Maintenance Therapy: Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity. Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    LY231514, Alimta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin: 75 mg/m² given intravenously on Day 1 for a maximum of 4 cycles.

    Number of subjects in period 1
    		Study Treatment Induction
    Started
    109
    Death (any cause) or Disease Progression
    21 [1]
    Received at Least One Dose of Study Drug
    109
    Completed
    94
    Not completed
    15
         Physician decision
    2
         Adverse event, non-fatal
    10
         Withdrawal by Subject
    2
         Entry Criteria Not Met
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who died or had disease progression are considered to have completed the phase. Of the 109 participants who started the Induction Therapy Period, 15 did not complete this phase.
    Period 2
    Period 2 title
    Maintienance Therapy Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Study Treatment Maintenance
    Arm description
    		 Maintenance Therapy: Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity. Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    LY231514, Alimta
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity.

    Number of subjects in period 2 [2]
    		Study Treatment Maintenance
    Started
    72
    Did not enter Maintenance Therapy Period
    22 [3]
    Completed
    46
    Not completed
    26
         Physician decision
    4
         Adverse event, non-fatal
    15
         Withdrawal by Subject
    5
         Protocol Violation
    1
         Lost to follow-up
    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: Participants who died or had disease progression are considered to have completed the phase. Participants who did not enter the Maintenance Therapy Period included: 21 participants who died (any cause) or had disease progression during the Induction Therapy Period, and 1 participant who had a performance status of 2.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Eight participants did not enter the Follow-Up Period: 4 participants died during the Induction Therapy Period and 1 died during the Maintenance Therapy Period; 2 participants withdrew (1 Induction, 1 Maintenance), 1 participant was lost to follow-up in the Maintenance Therapy Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study Treatment Induction
    Reporting group description
    		 Induction Therapy: Bevacizumab: 7.5 milligram per kilogram (mg/kg) given intravenously on Day 1 for four cycles (cycle=21 days) of Induction Therapy. Pemetrexed: 500 milligram per square meter (mg/m²) given intravenously on Day 1 for four cycles of Induction Therapy. Cisplatin: 75 mg/m² given intravenously on Day 1 for a maximum of 4 cycles. Maintenance Therapy: Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity. Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.

    Reporting group values
    		 Study Treatment Induction Total
    Number of subjects
    		 109 109
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 75 75
        From 65-84 years
    		 34 34
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.1 ± 8.8 -
    Gender, Male/Female
    Units: participants
        Female
    		 45 45
        Male
    		 64 64
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 108 108
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Region of Enrollment
    Units: Subjects
        Spain
    		 12 12
        Denmark
    		 19 19
        Germany
    		 25 25
        Italy
    		 35 35
        Sweden
    		 18 18
    ECOG Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status Classifies participants according to their functional impairment. Scores range from 0 (Fully Active) to 5 (Death): 0 - Fully Active 1 - Ambulatory, Restricted Strenuous Activity 2 - Ambulatory, No Work Activities 3 - Partially Confined to Bed, Limited Self Care 4 - Completely Disabled 5 - Death
    Units: Subjects
        ECOG 0
    		 59 59
        ECOG 1
    		 50 50
    Initial Pathological Diagnosis
    Non-Small Cell Lung Cancer (NSCLC)
    Units: Subjects
        Adenocarcinoma
    		 99 99
        Large Cell Lung Carcinoma
    		 3 3
        Poorly Differentiated NSCLC
    		 3 3
        Other
    		 4 4
    Stage of Disease
    According to American Joint Committee on Cancer (AJCC) Cancer Staging Manual, sixth edition (2002), stage of disease means how big the tumor is and how far it has spread. Stages range from 0 (not spread) to IV (spread throughout the body). Stage IIIB - the cancer has spread to nearby tissue or spread to far away lymph nodes but not spread to other organs Stage IV - the cancer has spread to other organs of the body such as the other lung, brain, or liver
    Units: Subjects
        Stage IIIB
    		 10 10
        Stage IV
    		 99 99
    Tobacco Use
    Units: Subjects
        Never Smoked
    		 15 15
        Ex-Smoker
    		 66 66
        Current Smoker
    		 28 28

    End points

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    End points reporting groups
    Reporting group title
    Study Treatment Induction
    Reporting group description
    		 Induction Therapy: Bevacizumab: 7.5 milligram per kilogram (mg/kg) given intravenously on Day 1 for four cycles (cycle=21 days) of Induction Therapy. Pemetrexed: 500 milligram per square meter (mg/m²) given intravenously on Day 1 for four cycles of Induction Therapy. Cisplatin: 75 mg/m² given intravenously on Day 1 for a maximum of 4 cycles. Maintenance Therapy: Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity. Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.
    Reporting group title
    Study Treatment Maintenance
    Reporting group description
    		 Maintenance Therapy: Bevacizumab: 7.5 mg/kg given intravenously on Day 1 of each cycle (cycle=21 days) and continued until progression or unacceptable toxicity. Pemetrexed: 500 mg/m² given intravenously on Day 1 of each cycle and continued until progression or unacceptable toxicity.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival [1]
    End point description
    Progression-Free Survival (PFS) is defined as the time from the date of study enrollment to the first date of objectively determined PD or death from any cause. PD is defined using Response Evaluation Criteria in Solid Tumours (RECIST) Guidelines (Version 1.0), as at least a 20% increase in the sum of longest diameter (LD) of target lesions, taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died as of the data cut-off date and who do not have objective PD, PFS will be censored at the date of the last objective progression-free disease assessment. For participants who receive subsequent systemic anticancer therapy, PFS will be censored at the date of the last objective progression-free disease assessment prior to post-discontinuation systemic therapy.
    End point type
    Primary
    End point timeframe
    From enrollment to the first date of objectively determined Progressive Disease (PD) or death from any cause (every other cycle during study treatment and then every 6 weeks during follow-up period)(Baseline up to 36.1 Months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are used to represent objective PFS from the date of study enrollment to time of event of PD or death and reported as median months with 90% confidence interval.
    End point values
    		 Study Treatment Induction
    Number of subjects analysed
    109
    Units: Months
        median (confidence interval 90%)
    6.9 (5.7 to 8.3)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival (OS) is defined as the time from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS will be censored at the last contact date.
    End point type
    Secondary
    End point timeframe
    From enrollment to the date of death from any cause (every cycle during study treatment, every 6 weeks during follow-up period until PD, and then at least every 3 Months) (Baseline up to 36.3 Months)
    End point values
    		 Study Treatment Induction
    Number of subjects analysed
    109
    Units: Months
        median (confidence interval 95%)
    14.7 (11.5 to 19.7)
    No statistical analyses for this end point

    Secondary: Percentage of participants with confirmed complete response or partial response during study treatment (Induction and Maintenance)

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    End point title
    		 Percentage of participants with confirmed complete response or partial response during study treatment (Induction and Maintenance)
    End point description
    Overall Response Rate (ORR) is defined as the percentage of participants whose best response is complete response (CR) or partial response (PR) per RECIST Guidelines, Version 1.0. CR is disappearance of all tumor lesions. PR is either a) at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LDs, or b) complete disappearance of target lesions, with persistence (but not worsening) of 1 or more nontarget lesions. In either case, no new lesions may have appeared.
    End point type
    Secondary
    End point timeframe
    From enrollment to objectively determined PD (assessment during study treatment completed at every other cycle till PD and at 30 day follow-up)(Baseline up to 104.1 Weeks)
    End point values
    		 Study Treatment Induction
    Number of subjects analysed
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    42.2 (32.8 to 52)
    No statistical analyses for this end point

    Secondary: Percentage of participants with confirmed response complete or partial response during the Induction treatment only

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    End point title
    		 Percentage of participants with confirmed response complete or partial response during the Induction treatment only
    End point description
    CR and PR defined per RECIST Guidelines, Version 1.0. CR is disappearance of all tumor lesions. PR is either a) at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LDs, or b) complete disappearance of target lesions, with persistence (but not worsening) of 1 or more nontarget lesions. In either case, no new lesions may have appeared.
    End point type
    Secondary
    End point timeframe
    From the time of study enrollment to the first date of objectively determined PD during the induction therapy (assessment during study treatment completed at every other cycle up to four cycles) (Baseline up to 4 cycles)
    End point values
    		 Study Treatment Induction
    Number of subjects analysed
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    34.9 (26 to 44.6)
    No statistical analyses for this end point

    Secondary: Percentage of participants with confirmed complete response or partial response during the maintenance therapy only

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    End point title
    		 Percentage of participants with confirmed complete response or partial response during the maintenance therapy only
    End point description
    CR and PR defined per RECIST Guidelines, Version 1.0. CR is disappearance of all tumor lesions. PR is either a) at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LDs, or b) complete disappearance of target lesions, with persistence (but not worsening) of 1 or more nontarget lesions. In either case, no new lesions may have appeared.
    End point type
    Secondary
    End point timeframe
    From the start of the maintenance to the first date of objectively determined PD during the maintenance therapy (assessment during maintenance treatment completed at every other cycle till PD and at 30 day follow-up)(Cycle 5 up to 104.1 Weeks)
    End point values
    		 Study Treatment Maintenance
    Number of subjects analysed
    72
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.1 (4.9 to 20.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    H3E-EW-S125
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 + Bevacizumab 7.5 m
    Reporting group description
    		 -

    Serious adverse events
    		 Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 + Bevacizumab 7.5 m
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 109 (35.78%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    metastatic pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    tumour pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    thrombosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    impaired healing
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    5 / 109 (4.59%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    haemoptysis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    idiopathic pulmonary fibrosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    pneumonia aspiration
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    pulmonary embolism
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    platelet count decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    white blood cell count decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    atrial fibrillation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    left ventricular dysfunction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    pericardial effusion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    coma
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    syncope
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    transient global amnesia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    lymphopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    constipation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    gastrointestinal perforation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    large intestine perforation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    nausea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    renal failure acute
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    bone pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    bronchopneumonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    postoperative wound infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    cachexia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    decreased appetite
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 + Bevacizumab 7.5 m
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 109 (92.66%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    23 / 109 (21.10%)
         occurrences all number
    26
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    12
    chest pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    10
    fatigue
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    51 / 109 (46.79%)
         occurrences all number
    63
    influenza like illness
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    7
    mucosal inflammation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    14 / 109 (12.84%)
         occurrences all number
    20
    oedema peripheral
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    14 / 109 (12.84%)
         occurrences all number
    14
    pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    7
    pyrexia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    17 / 109 (15.60%)
         occurrences all number
    34
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    22 / 109 (20.18%)
         occurrences all number
    29
    dysphonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    8
    dyspnoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    16 / 109 (14.68%)
         occurrences all number
    22
    epistaxis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    28 / 109 (25.69%)
         occurrences all number
    38
    oropharyngeal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    9
    rhinorrhoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    10
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    6
    insomnia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    12 / 109 (11.01%)
         occurrences all number
    12
    Investigations
    blood creatinine increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    7
    haemoglobin decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    9
    weight decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    11
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    10 / 109 (9.17%)
         occurrences all number
    11
    dysgeusia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    10 / 109 (9.17%)
         occurrences all number
    10
    headache
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    19 / 109 (17.43%)
         occurrences all number
    22
    neuropathy peripheral
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    9
    paraesthesia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    10 / 109 (9.17%)
         occurrences all number
    11
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    17 / 109 (15.60%)
         occurrences all number
    20
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    9 / 109 (8.26%)
         occurrences all number
    9
    leukopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    31
    neutropenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    22 / 109 (20.18%)
         occurrences all number
    60
    Ear and labyrinth disorders
    tinnitus
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    12
    Eye disorders
    lacrimation increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    16 / 109 (14.68%)
         occurrences all number
    19
    Gastrointestinal disorders
    constipation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    39 / 109 (35.78%)
         occurrences all number
    54
    diarrhoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    25 / 109 (22.94%)
         occurrences all number
    29
    dyspepsia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    14 / 109 (12.84%)
         occurrences all number
    15
    gastritis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    7
    nausea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    64 / 109 (58.72%)
         occurrences all number
    128
    stomatitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    17 / 109 (15.60%)
         occurrences all number
    25
    vomiting
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    25 / 109 (22.94%)
         occurrences all number
    45
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    11 / 109 (10.09%)
         occurrences all number
    16
    rash
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    11
    Renal and urinary disorders
    proteinuria
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    10 / 109 (9.17%)
         occurrences all number
    14
    back pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    6
    bone pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    12 / 109 (11.01%)
         occurrences all number
    12
    musculoskeletal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    7
    myalgia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    10
    pain in extremity
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 109 (6.42%)
         occurrences all number
    9
    Infections and infestations
    infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    7
    nasopharyngitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 109 (5.50%)
         occurrences all number
    7
    upper respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    8 / 109 (7.34%)
         occurrences all number
    10
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    22 / 109 (20.18%)
         occurrences all number
    29

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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