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    Clinical Trial Results:
    NGR015: Randomized double-blind phase III study of NGR-hTNF plus best investigator s choice (BIC) versus placebo plus BIC in previously treated patients with advanced malignant pleural mesothelioma (MPM)

    Summary
    EudraCT number
    		 2009-016879-29
    Trial protocol
    		 IT   AT   IE   GB   NL   BE   SE   ES  
    Global end of trial date
    18 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2019
    First version publication date
    20 Jun 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NGR015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01098266
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MolMed S.p.A.
    Sponsor organisation address
    Via Olgettina, 58, Milano, Italy, 20132
    Public contact
    Clinical Operations, MolMed S.p.A., 0039 02212771, clinical.operations@molmed.com
    Scientific contact
    Clinical Operations, MolMed S.p.A., 0039 02212771, clinical.operations@molmed.com
    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
    29 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare overall survival (OS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC.
    Protection of trial subjects
    The responsible investigator will ensure that this study is conducted in full conformance with either the principles of the "Declaration of Helsinki" (as amended in Tokyo, Venice, Hong Kong, South Africa and Edinburgh) or the laws and regulations of the country in which the study was conducted, whichever affords the greater protection to the individual. The protocol has been written and the study will be conducted in conformity to the "Guideline for Good Clinical Practice" (recommended for adoption at step 4 of the ICH process on 1 May 1996 and on 10 June 1996 by the ICH Steering Committee and acknowledged as ministerial decree, on 15 July 1997, by the Italian Ministry of Health). The study descriptions were submitted to the IEC before study start. All patient received all the information about the study and they gave their written acceptance through informed consent signature. Sponsor provided a full insurance coverage. All personal data complied with local law for privacy protection. All data recorded has been coded.
    Background therapy
    		 Patients previously treated with a pemetrexed-based chemotherapy regimen for advanced or metastatic disease.
    Evidence for comparator
    		 Considering the toxicity profile of NGR-hTNF characterized by mild-to-moderate constitutional symptoms registered in the NGR010 phase II trial in previously treated MPM patients, as well as the disease control observed in about half of the patients and maintained for more than four months and more than nine months in the triweekly and weekly cohorts, respectively, seems justified to compare in a randomized phase III trial the time-related efficacy of NGR-hTNF 0.8 μg/m2 weekly against best investigator’s choice (or option) in advanced MPM patients progressing after a standard pemetrexed-based chemotherapy. Currently, there are no regulatory-approved or widely-accepted treatment options for patients failing a standard pemetrexed-based chemotherapy regimen. For this reason, the best supportive care (BSC) alone might be considered as a standard reference for a randomized phase III trial in this setting.
    Actual start date of recruitment
    12 Apr 2010
    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 States: 25
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Egypt: 36
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 95
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 163
    Worldwide total number of subjects
    400
    EEA total number of subjects
    330
    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)
    179
    From 65 to 84 years
    219
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study period: 12 April 2010 (first enrollment); 21 January 2013 (last enrollment). 15 clinical sites in Italy, 10 in United Kingdom, 7 in United States, 4 in Belgium, 2 in Canada, 2 in Netherland, 2 in Poland, 1 in Egypt, 1 in Ireland and 1 in Sweden.

    Pre-assignment
    Screening details
    		 14 enrolled patients (7 NGR-hTNF and 7 placebo) dropped out before receiving treatment for the following reason: - early symptomatic deterioration (physician decision, n=8) - death (n=5) - withdrawal of informed consent (n=1)

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy
    Arm description
    		 Group A will receive NGR-hTNF plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - NGR-hTNF: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12
    Arm type
    		 Experimental

    Investigational medicinal product name
    NGR-hTNF
    Investigational medicinal product code
    MM102
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Before infusion to patients, NGR-hTNF in citrate buffer (50mM sodium citrate, 35 mg/ml mannitol, 10 mg/ml sucrose, pH 6.2) will be diluted to the appropriate concentration with 0.9% NaCl containing 1 mg/ml human serum albumin (HSA). The patients will receive NGR-hTNF every week by 60-minute intravenous infusion at 0.8 μg/m² until progressive disease. Acetaminophen/paracetamol 1000 mg p.o. or i.v. is recommended as prophylaxis 30 to 60 minutes prior starting each infusion of NGR-hTNF. No concomitant hydration is allowed during the NGR-hTNF infusion period. No chronic or high dose corticosteroid therapy is allowed during the study treatment period. Where applicable and according to the Institutional clinical practice, patients should receive Best Supportive Care (BSC). BSC includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At Investigator discretion, Doxorubicin (60-75 mg/m2 iv infusion on day 1 every 3 weeks, for a maximum of 6 cycles) might be administered in combination with NGR-hTNF one hour after the end of NGRhTNF administration.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At Investigator discretion, Gemcitabine (1,000-1,250 mg/m2 iv infusion, on days 1 and 8, every 3 weeks, for a maximum of 6 cycles) might be administered in combination with NGR-hTNF one hour after the end of NGRhTNF administration.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft, Concentrate for solution for infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    At Investigator discretion, Vinorelbine (25 mg/m2 iv or 60 mg/m2 per os if approved in the Country on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)) might be administered in combination with NGR-hTNF one hour after the end of NGRhTNF administration.

    Arm title
    		 Arm B - Placebo + BSC ± single-agent chemotherapy
    Arm description
    		 Group B will receive placebo plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - placebo: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (orweekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NGR-hTNF placebo consisted of a vehicle for NGR-hTNF without the active ingredients. The quantitative composition of the placebo consisted of 50mM citrate buffer, 35 mg/ml mannitol and 10 mg/ml sucrose in 3 ml type I glass vials (1 ml/vial). The patients will receive placebo every week by 60-minute intravenous infusion at 0.8 μg/m² until progressive disease. Acetaminophen/paracetamol 1000 mg p.o. or i.v. is recommended as prophylaxis 30 to 60 minutes prior starting each infusion of placebo. No concomitant hydration is allowed during the placebo infusion period. No chronic or high dose corticosteroid therapy is allowed during the study treatment period. Where applicable and according to the Institutional clinical practice, patients should receive Best Supportive Care (BSC). BSC includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At Investigator discretion, Doxorubicin (60-75 mg/m2 iv infusion on day 1 every 3 weeks, for a maximum of 6 cycles) might be administered in combination with placebo one hour after the end of placebo administration.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    At Investigator discretion, Gemcitabine (1,000-1,250 mg/m2 iv infusion, on days 1 and 8, every 3 weeks, for a maximum of 6 cycles) might be administered in combination with placebo one hour after the end of placebo administration.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft, Concentrate for solution for infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    At Investigator discretion, Vinorelbine (25 mg/m2 iv or 60 mg/m2 per os if approved in the Country on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks)) might be administered in combination with placebo one hour after the end of placebo administration.

    Number of subjects in period 1
    		Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Started
    200
    200
    Completed
    193
    193
    Not completed
    7
    7
         Consent withdrawn by subject
    1
    -
         Physician decision
    3
    5
         Death
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy
    Reporting group description
    		 Group A will receive NGR-hTNF plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - NGR-hTNF: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12

    Reporting group title
    Arm B - Placebo + BSC ± single-agent chemotherapy
    Reporting group description
    		 Group B will receive placebo plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - placebo: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (orweekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12)

    Reporting group values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy Total
    Number of subjects
    		 200 200 400
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 92 87 179
        From 65-84 years
    		 106 113 219
        85 years and over
    		 2 0 2
    Age continuous
    Units: years
        median (full range (min-max))
    		 65 (25 to 89) 67 (31 to 81) -
    Gender categorical
    Units: Subjects
        Female
    		 44 55 99
        Male
    		 156 145 301

    End points

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    End points reporting groups
    Reporting group title
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy
    Reporting group description
    		 Group A will receive NGR-hTNF plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - NGR-hTNF: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (or weekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12

    Reporting group title
    Arm B - Placebo + BSC ± single-agent chemotherapy
    Reporting group description
    		 Group B will receive placebo plus the current treatment option (best supportive care BSC with or without single-agent chemotherapy): - placebo: 0.8 μg/m² as 60-minute iv infusion every week; - BSC: where applicable and according to clinical practice, includes antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritional support, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis; - Investigator’s Choice: at Investigator discretion, one of the following single-agent chemotherapy might be administered in combination: a) Doxorubicin: 60-75 mg/m2 every 3 weeks, for a maximum of 6 cycles, OR b) Gemcitabine: 1,000-1,250 mg/m2 on days 1 and 8, every 3 weeks, for a maximum of 6 cycles, OR c) Vinorelbine: 25 mg/m2 iv on days 1 and 8 every 3 weeks, for a maximum of 6 cycles (orweekly for 12 weeks) or, if approved in the Country, 60 mg/m2 per os on days 1 and 8 every 3 weeks for a maximum of 6 cycles (or weekly for 12)

    Primary: Overall survival (OS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Overall survival (OS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    The overall survival (OS) was defined as the time from the date of randomization until the date of death due to any cause or the last date the patient was known to be alive. The log-rank test (unstratified) will be used to compare the two treatment arms. In addition, a stratified version of the log-rank test will be performed with the stratification factors used for randomization. Kaplan-Meier curves will be displayed, and median survival estimates and confidence limits of them will be given.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of death due to any cause or the last date the patient was known to be alive.
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200
    200
    Units: Months
        median (confidence interval 95%)
    8.5 (7.2 to 9.9)
    8.0 (6.6 to 8.9)
    Statistical analysis title
    		 Unstratified log-rank test p-value
    Comparison groups
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy v Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.18
    Variability estimate
    Standard deviation

    Secondary: Progression-free survival (PFS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Progression-free survival (PFS) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    Progression-free survival (PFS) was defined as the time from the date of randomization until disease progression, or death due to any cause. Patients with no tumor assessments after baseline but who are still alive at the time of the clinical cut-off will be censored at day of randomization. The log-rank test (unstratified and stratified) was used at an alpha level of 5% to test for differences in PFS between the two treatment arms. Kaplan-Meier curves and estimates were provided. Cox regression analyses (unstratified and stratified) was performed to assess the influence of baseline covariates in an exploratory manner.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until disease progression, or death due to any cause.
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200
    200
    Units: Months
        median (confidence interval 95%)
    3.4 (2.7 to 4.1)
    3.0 (2.3 to 3.7)
    Statistical analysis title
    		 Unstratified log-rank test p-value
    Statistical analysis description
    The log-rank test (unstratified and stratified) was used at an alpha level of 5% to test for differences in PFS between the two treatment arms. Kaplan-Meier curves and estimates were provided.
    Comparison groups
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy v Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.65
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.17
    Notes
    [1] - Cox regression analyses (unstratified and stratified) was performed to assess the influence of baseline covariates in an exploratory manner.

    Secondary: Disease control rate (DCR) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Disease control rate (DCR) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    Disease control rate (DCR) is defined as the percentage of patients who have a best response rating of complete response, partial response, or stable disease. The tumor thickness perpendicular to the chest wall or mediastinum will be assessed according to modified RECIST criteria for MPM. The difference in DCR between the two treatment arms will be tested using a chi-squared test with 95% confidence intervals calculated in each treatment arm.
    End point type
    Secondary
    End point timeframe
    At any time.
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200
    200
    Units: Subjects
        number (not applicable)
    114
    109
    Statistical analysis title
    		 Fisher exact test p-value
    Statistical analysis description
    The difference in DCR between the two treatment arms were tested using a chi-squared test with 95% confidence intervals calculated in each treatment arm.
    Comparison groups
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy v Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.62
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.68
    Notes
    [2] - Logistic regression analyses were performed to assess the influence of baseline covariates in an exploratory manner.

    Secondary: Duration of disease control in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Duration of disease control in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    In the subset of patients who achieve disease control, the duration of disease control was measured from the date of randomization until disease progression, or death due to any cause. For the duration of disease control, the same methods were used as for PFS. Kaplan-Meier curves and estimates were provided and the log-rank test were used to assess differences between the two treatment groups, even though no formal hypothesis testing were performed, as this analysis was based on a non-randomized subset of patients.
    End point type
    Secondary
    End point timeframe
    The duration of disease control was measured from the date of randomization until disease progression, or death due to any cause.
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200
    200
    Units: Subjects
    84
    76
    No statistical analyses for this end point

    Secondary: Safety and Toxicity profile related to NGR-hTNF according to NCI-CTCAE Criteria (Version 4.02)

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    End point title
    		 Safety and Toxicity profile related to NGR-hTNF according to NCI-CTCAE Criteria (Version 4.02)
    End point description
    Adverse events were recorded according to the CTC-AE v .4.02 (CTC reference: http://ctep.cancer.gov/reporting/ctc.html) on the case report forms (CRFs); the investigator decided if those events were drug related and his decision was recorded on the forms for all adverse event. Adverse events were displayed in standard frequency tables. For laboratory parameters, descriptive summary tables of change from baseline over time based on SI units were produced. Descriptive summary tables of change from baseline over time were provided for vital signs parameters.
    End point type
    Secondary
    End point timeframe
    During the study (from day 1 to 28 days after last treatment).
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    193 [3]
    193 [4]
    Units: Subjects
    191
    185
    Notes
    [3] - The safety data referred to patients of both arms who received at least one treatment
    [4] - The safety data referred to patients of both arms who received at least one treatment
    No statistical analyses for this end point

    Secondary: Quality of Life (QoL) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Quality of Life (QoL) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    Quality of life assessment was performed by using a questionnaire according to Lung Cancer Symptom Scale (LCSS). The LCSS is designed as a disease and site-specific measure of quality of life (QoL) particularly for use in clinical trials. It evaluates six major symptoms (loss of appetite, fatigue, cough, dyspnea, hemoptysis, and pain) associated with lung malignancies and their effect on overall symptomatic distress, functional activities, and global QoL. Within this trial the questionnaire according to LCSS was only recorded by the patient (patient’s scale). Symptomatic progression was defined as a worsening in the average symptom burden index by 25%. Time to symptomatic progression was defined as time from randomization to the date of the LCSS assessment on which symptomatic progression was identified.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks.
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200 [5]
    200 [6]
    Units: Subjects
    175
    185
    Notes
    [5] - After one treatment cycle.
    [6] - After one treatment cycle
    Statistical analysis title
    		 Stratified log-rank test p-value
    Comparison groups
    Arm A - NGR-hTNF + BSC ± single-agent chemotherapy v Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.59
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.26

    Secondary: Medical Care Utilization (MCU) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC

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    End point title
    		 Medical Care Utilization (MCU) in patients randomized to NGR-hTNF plus BIC versus patients randomized to placebo plus BIC
    End point description
    Medical resource use data collected will be used in health economic analyses where it may be combined with other data from other sources such as cost data or other clinical parameters.
    End point type
    Secondary
    End point timeframe
    on ongoing-basis
    End point values
    		 Arm A - NGR-hTNF + BSC ± single-agent chemotherapy Arm B - Placebo + BSC ± single-agent chemotherapy
    Number of subjects analysed
    200
    200
    Units: Patient
    187
    186
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    FconsAll Serious Adverse Events (SAE), related or not to the protocol treatment, occurring during the trial and within 28 days after the last treatment administration, were reported by MolMed S.p.A. within 24 hours of the initial observation of the event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    NGR-hTNF + BSC ± single-agent chemotherapy
    Reporting group description
    		 safety analyses were done on 386 patients (safety population), since 14 patients (7 NGR-hTNF and 7 placebo)

    Reporting group title
    Placebo + BSC ± single-agent chemotherapy
    Reporting group description
    		 safety analyses were done on 386 patients (safety population), since 14 patients (7 NGR-hTNF and 7 placebo)

    Serious adverse events
    		 NGR-hTNF + BSC ± single-agent chemotherapy Placebo + BSC ± single-agent chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 193 (29.02%)
    54 / 193 (27.98%)
         number of deaths (all causes)
    149
    149
         number of deaths resulting from adverse events
    12
    13
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Paraneoplastic fever
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain mets
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural mesothelioma
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (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
    Chills
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 193 (1.55%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Hyperpyrexia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic ulcer to left heel
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 193 (1.55%)
    3 / 193 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deterioration of clinical status
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Admitted for pain control
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    4 / 193 (2.07%)
    5 / 193 (2.59%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    4 / 4
    5 / 5
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 193 (2.07%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 193 (1.04%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infection (chest) with normal ANC
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Uncertain study medication dose delivered
         subjects affected / exposed
    4 / 193 (2.07%)
    9 / 193 (4.66%)
         occurrences causally related to treatment / all
    4 / 4
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug infusion reaction
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occipital trauma
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 193 (0.52%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac arrest
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior sagittal sinus thrombosis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right hemispheric cerebrovascular accident
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Jacksonian seizure
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 193 (1.04%)
    4 / 193 (2.07%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic fever
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 193 (1.04%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal ascites
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Abnormal renal function
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain right chest wall + right shoulder
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infection - source unknown
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral gastroenteritis
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NGR-hTNF + BSC ± single-agent chemotherapy Placebo + BSC ± single-agent chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    190 / 193 (98.45%)
    185 / 193 (95.85%)
    Investigations
    Transaminases increased
         subjects affected / exposed
    14 / 193 (7.25%)
    7 / 193 (3.63%)
         occurrences all number
    37
    20
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 193 (6.22%)
    12 / 193 (6.22%)
         occurrences all number
    16
    15
    Hypotension
         subjects affected / exposed
    10 / 193 (5.18%)
    7 / 193 (3.63%)
         occurrences all number
    12
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 193 (5.70%)
    12 / 193 (6.22%)
         occurrences all number
    12
    14
    Dysgeusia
         subjects affected / exposed
    10 / 193 (5.18%)
    6 / 193 (3.11%)
         occurrences all number
    10
    7
    Headache
         subjects affected / exposed
    15 / 193 (7.77%)
    13 / 193 (6.74%)
         occurrences all number
    16
    14
    Pheripheral neuropathy
         subjects affected / exposed
    12 / 193 (6.22%)
    12 / 193 (6.22%)
         occurrences all number
    20
    15
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    104 / 193 (53.89%)
    23 / 193 (11.92%)
         occurrences all number
    462
    29
    Fatigue
         subjects affected / exposed
    93 / 193 (48.19%)
    94 / 193 (48.70%)
         occurrences all number
    166
    180
    Pain
         subjects affected / exposed
    91 / 193 (47.15%)
    89 / 193 (46.11%)
         occurrences all number
    179
    184
    Pyrexia
         subjects affected / exposed
    48 / 193 (24.87%)
    39 / 193 (20.21%)
         occurrences all number
    103
    67
    Oedema
         subjects affected / exposed
    26 / 193 (13.47%)
    25 / 193 (12.95%)
         occurrences all number
    31
    29
    Mucosal inflammation
         subjects affected / exposed
    20 / 193 (10.36%)
    17 / 193 (8.81%)
         occurrences all number
    29
    23
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    57 / 193 (29.53%)
    60 / 193 (31.09%)
         occurrences all number
    162
    119
    Anaemia
         subjects affected / exposed
    34 / 193 (17.62%)
    42 / 193 (21.76%)
         occurrences all number
    58
    79
    Thrombocytopenia
         subjects affected / exposed
    26 / 193 (13.47%)
    23 / 193 (11.92%)
         occurrences all number
    56
    47
    Leukopenia
         subjects affected / exposed
    24 / 193 (12.44%)
    20 / 193 (10.36%)
         occurrences all number
    85
    24
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    61 / 193 (31.61%)
    62 / 193 (32.12%)
         occurrences all number
    122
    130
    Constipation
         subjects affected / exposed
    42 / 193 (21.76%)
    45 / 193 (23.32%)
         occurrences all number
    65
    65
    Vomiting
         subjects affected / exposed
    33 / 193 (17.10%)
    38 / 193 (19.69%)
         occurrences all number
    61
    81
    Diarrhoea
         subjects affected / exposed
    20 / 193 (10.36%)
    36 / 193 (18.65%)
         occurrences all number
    39
    58
    Dyspepsia
         subjects affected / exposed
    10 / 193 (5.18%)
    11 / 193 (5.70%)
         occurrences all number
    12
    13
    Abdominal discomfort
         subjects affected / exposed
    1 / 193 (0.52%)
    11 / 193 (5.70%)
         occurrences all number
    1
    12
    Respiratory, thoracic and mediastinal disorders
    Dysponoea
         subjects affected / exposed
    63 / 193 (32.64%)
    56 / 193 (29.02%)
         occurrences all number
    94
    80
    Cough
         subjects affected / exposed
    39 / 193 (20.21%)
    47 / 193 (24.35%)
         occurrences all number
    59
    71
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 193 (6.22%)
    4 / 193 (2.07%)
         occurrences all number
    12
    4
    Rush
         subjects affected / exposed
    11 / 193 (5.70%)
    8 / 193 (4.15%)
         occurrences all number
    15
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 193 (5.70%)
    12 / 193 (6.22%)
         occurrences all number
    12
    12
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    13 / 193 (6.74%)
    10 / 193 (5.18%)
         occurrences all number
    15
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    46 / 193 (23.83%)
    51 / 193 (26.42%)
         occurrences all number
    68
    76
    Hypocalcaemia
         subjects affected / exposed
    12 / 193 (6.22%)
    5 / 193 (2.59%)
         occurrences all number
    21
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jan 2010
    Version B:It has been included a sub-study for Vinorelbine administration, to evaluate the safety of the combination with NGR-hTNF (protocol section 6.5)
    02 Sep 2010
    Version C:This was a local amendment for UK clinical sites only, in which has been added the paragraph for Special Warnings during and after treatment on contraceptive measures to be used (protocol section 6.7)
    15 Sep 2011
    Version D*:It has been included the type of chemotherapy, as a stratification factor for patients candidate for chemotherapy (protocol sections 3 and 6.1) It has been defined the use of oral Vinorelbine only if approved in the Country. (protocol sections 3, 5.4 and 6.5) It has been included in the inclusion criteria No. 3, that patients previously treated with anthracyclines should not receive Doxorubicin, as Investigator’s choice (protocol section 4.2) It has been increased from 14 to 28 days the wash-out period from radiotherapy, in the inclusion criteria No. 8 (protocol section 4.2) It has been added the 12-lead EKG for evaluation of QTc interval at baseline, week 6, 12, 18, 24 and at the end of treatment (protocol sections 6.1, 6.2, 6.3 and 7) It has been included in the collection of adverse events and serious adverse events, also those related to disease under study, such as progression, hospitalization, signs and symptoms (protocol section 10.3.2) *This amendment has been suggested by FDA
    29 Mar 2012
    Version E:It has been concluded the sub-study for Vinorelbine administration and defined the lowest dose level of Vinorelbine to be used in combination with NGRhTNF/ placebo. (protocol section 6.3)

    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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