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    Clinical Trial Results:
    NGR014: Randomized phase II study of NGR-hTNF in combination with standard chemotherapy versus standard chemotherapy alone in previously untreated patients with advanced non-small cell lung cancer (NSCLC).

    Summary
    EudraCT number
    		 2008-002703-20
    Trial protocol
    		 IT  
    Global end of trial date
    30 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2019
    First version publication date
    21 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NGR014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MolMed S.p.A.
    Sponsor organisation address
    Via Olgettina, 58, Milan, 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
    24 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect on progression-free survival (PFS) of NGR-hTNF administered at low dose (0.8 μg/m2) in combination with standard chemotherapy as compared to standard chemotherapy alone.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The study was performed in compliance with Good Clinical Practices (CPMP/ICH/135/95), and the essential documents are archived as required by the applicable regulatory requirements. The study and any amendments were reviewed by an Independent Ethics Committees or Institutional Review Boards
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jul 2009
    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
    Italy: 121
    Worldwide total number of subjects
    121
    EEA total number of subjects
    121
    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)
    78
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was performed in a total of 4 investigational study sites in Italy. 1. Department of Medical Oncology, Onco-Haematology Unit, San Raffaele Hospital, Milan, was the coordinator centre. 2. Istituto Nazionale dei Tumori (INT), Milan (IT) 3. A.O.U. San Martino (IST), Genoa (IT) 4. Istituto Europeo Oncologico (IEO), Milan (IT)

    Pre-assignment
    Screening details
    		 Overall, 121 consented and screened patients were enrolled. 62 patients were randomised to Arm A, whereas 59 were randomised to Arm B. 6 patients (2 in arm A and 4 in arm B) dropped out before receiving treatment for the following reasons: physician decision (n=2), withdrawal of ICF (n=2), death (n=1), poor compliance (n=1).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy)
    Arm description
    		 In patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 intravenous (iv) infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. In patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 iv infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NGR-hTNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.8 μg/m2 iv infusion over 1 hour every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1,250 mg/m2 iv infusion (1 hour after the end of NGR-hTNF infusion) on days 1 and 8 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 iv infusion (1 hour after the end of NGR-hTNF infusion) on day 1 every 3 weeks for a maximum of 6 cycles

    Arm title
    		 Arm B (control arm = standard chemotherapy)
    Arm description
    		 Patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. Patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.
    Arm type
    		 control arm

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles

    Number of subjects in period 1 [1]
    		Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Started
    60
    55
    Completed
    48
    24
    Not completed
    12
    31
         Adverse event, serious fatal
    2
    2
         Consent withdrawn by subject
    1
    1
         Physician decision
    5
    5
         Disease progression
    -
    15
         Adverse event, non-fatal
    3
    6
         Other
    1
    1
         Need for surgery
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The analyses were performed only on treated patients.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (experimental arm = NGR-hTNF + standard chemotherapy)
    Reporting group description
    		 In patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 intravenous (iv) infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. In patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 iv infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.

    Reporting group title
    Arm B (control arm = standard chemotherapy)
    Reporting group description
    		 Patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. Patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.

    Reporting group values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy) Total
    Number of subjects
    		 60 55 115
    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)
    		 42 32 74
        From 65-84 years
    		 18 23 41
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.15 ± 8.52 61.75 ± 8.64 -
    Gender categorical
    Units: Subjects
        Female
    		 24 19 43
        Male
    		 36 36 72
    Histology
    Units: Subjects
        Squamous
    		 17 15 32
        Non-squamous
    		 43 40 83

    End points

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    End points reporting groups
    Reporting group title
    Arm A (experimental arm = NGR-hTNF + standard chemotherapy)
    Reporting group description
    		 In patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 intravenous (iv) infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. In patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma) the following regimen was recommended: - NGR-hTNF administered at 0.8 μg/m2 iv infusion over 1 hour every 3 weeks until progression of disease, followed (1 hour after the end of NGR-hTNF infusion) by: - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.

    Reporting group title
    Arm B (control arm = standard chemotherapy)
    Reporting group description
    		 Patients with squamous histology (including also generic diagnosis of NSCLC without further subtype classification): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Gemcitabine 1,250 mg/m2 iv infusion on days 1 and 8 every 3 weeks for a maximum of 6 cycles. Patients with nonsquamous histology (including adenocarcinoma and large-cell carcinoma): - Cisplatin 80 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles; - Pemetrexed 500 mg/m2 iv infusion on day 1 every 3 weeks for a maximum of 6 cycles.

    Primary: Progression-free survival (PFS), defined as the time from the date of randomization until disease progression, or death due to any cause.

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    End point title
    		 Progression-free survival (PFS), defined as the time from the date of randomization until disease progression, or death due to any cause.
    End point description
    Defined as the time from the date of randomization until disease progression, or death due to any couse or the last patient was konwn to be alive. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (Recist v1.0), as a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition torelative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm. In addition the appearance of one or more new lesions was also considered progression. The results of PFS in the PP set, computed with the Kaplan-Meier method, are presented as Median (95% CI)
    End point type
    Primary
    End point timeframe
    every 6 weeks, up to the last treatment cycle.
    End point values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Number of subjects analysed
    60
    55
    Units: days
    163
    181
    Statistical analysis title
    		 Progression-free survival (PFS)
    Statistical analysis description
    The median PFS was 163 days (95% CI: 107-198 days) in arm A and 181 days (95% CI: 133-207 days) in arm B. One (1.7%) patient in arm A and 2 (3.6%) in arm B were censored, while events (i.e. failures) were reported in 59 (98.3%) patients in arm A and in 53 (96.4%) in arm B. The comparison between arms in the log rank model did not show statistically significant differences (p = 0.38).
    Comparison groups
    Arm A (experimental arm = NGR-hTNF + standard chemotherapy) v Arm B (control arm = standard chemotherapy)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.38
    Method
    		 Logrank
    Confidence interval

    Secondary: Objective response rate (ORR), according to RECIST 1.0 criteria.

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    End point title
    		 Objective response rate (ORR), according to RECIST 1.0 criteria.
    End point description
    Objective response rate (ORR), according to RECIST 1.0 criteria. Tumor response rate was defined as the best overall response (Complete Response, Partial Response, Stable Disease or Progressive Disease) achieved. The best overall response was calculated as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) or until the start of another treatment.
    End point type
    Secondary
    End point timeframe
    every 6 weeks, up to the last treatment cycle.
    End point values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Number of subjects analysed
    60
    55
    Units: subjects
        Complete response
    0
    1
        Partial response
    14
    13
        Stable disease
    32
    30
        Progressive disease
    13
    5
        Not evaluable
    1
    6
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    From the time measurement criteria were met for Complete Response/Partial Response (whichever was first recorded) until the first date that recurrent or progressive disease was objectively documented or death for any cause.
    End point type
    Secondary
    End point timeframe
    every 6 weeks, up to the last treatment cycle.
    End point values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Number of subjects analysed
    60
    55
    Units: days
    114
    188
    Statistical analysis title
    		 Duration of Response (DR).
    Statistical analysis description
    The median duration of response was 114 days (95% CI: 67-142 days) in arm A and 188 days (95% CI: 97-210 days) in arm B. None (0.0%) of patients in arm A and 1 (5.9%) patient in arm B were censored, while events (i.e. failures) were reported in all 22 (100.0%) patients in arm A and in 16 (94.1%) in arm B. The comparison between arms in the log rank model showed a statistically significant difference (p = 0.044).
    Comparison groups
    Arm A (experimental arm = NGR-hTNF + standard chemotherapy) v Arm B (control arm = standard chemotherapy)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.044
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall Survival (OS), defined as the time from the date of randomization until death due to any cause. End point related data are reported as median (95% CI)
    End point type
    Secondary
    End point timeframe
    Assessed every 6 weeks, up to the completion of the last treatment cycle or in case of discontinuation of the treatment before disease progression. OS was assessed every 12 weeks after the last treatment cycle up to study completion (an everage 8 years).
    End point values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Number of subjects analysed
    60
    55
    Units: days
    360
    380
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    The median OS was 360 days (95% CI: 245-476 days) in arm A and 380 days (95% CI: 294-596 days) in arm B. Four (6.7%) patients in arm A and 7 (12.7%) in arm B were censored, while events (i.e. deaths) were reported in 56 (93.3%) patients in arm A and in 48 (87.3%) in arm B. The comparison between arms in the log rank model did not show statistically significant differences (p = 0.217).
    Comparison groups
    Arm B (control arm = standard chemotherapy) v Arm A (experimental arm = NGR-hTNF + standard chemotherapy)
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.217
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Adverse Events

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    End point title
    		 Number of Adverse Events
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a casual relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment emergent adverse events (TEAEs) were defined as AEs that started or worsened in severity on or after the first dose of study medication, regardless of relationship with study treatment. All adverse events will be recorded according to CTC version 3.0 (CTC reference: http://ctep;info;nih.gov/CTC3/default.htm) on the case report forms (CRFs); the investigator will decide if those events are drug related and his decision will be recorded on the forms for all adverse events.
    End point type
    Secondary
    End point timeframe
    Assessed every 3 weeks, up to the completion of the last treatment cycle. After the last treatment cycle adverse events were registered for the following 28 days.
    End point values
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Number of subjects analysed
    60
    55
    Units: Number of patients
        with fatal TEAEs
    2
    2
        with at least one TESAE
    11
    11
        with at least one TEAE
    59
    53
        with at least one TEAE related to NGR-hTNF
    34
    0
        with at least one TEAE related to chemotherapy
    58
    51
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed every 3 weeks, up to the completion of the last treatment cycle. After the last treatment cycle adverse events were registered for the following 28 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A (experimental arm = NGR-hTNF + standard chemotherapy)
    Reporting group description
    		 -

    Reporting group title
    Arm B (control arm = standard chemotherapy)
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 60 (18.33%)
    11 / 55 (20.00%)
         number of deaths (all causes)
    56
    48
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Thrombosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group Performance Status Worsened
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tendon Rupture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Haemorrhagic
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (experimental arm = NGR-hTNF + standard chemotherapy) Arm B (control arm = standard chemotherapy)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 60 (98.33%)
    53 / 55 (96.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 60 (13.33%)
    6 / 55 (10.91%)
         occurrences all number
    13
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 60 (61.67%)
    32 / 55 (58.18%)
         occurrences all number
    80
    58
    Chills
         subjects affected / exposed
    31 / 60 (51.67%)
    0 / 55 (0.00%)
         occurrences all number
    49
    0
    Pain
         subjects affected / exposed
    17 / 60 (28.33%)
    15 / 55 (27.27%)
         occurrences all number
    29
    25
    Mucosal Inflammation
         subjects affected / exposed
    12 / 60 (20.00%)
    11 / 55 (20.00%)
         occurrences all number
    16
    19
    Pyrexia
         subjects affected / exposed
    12 / 60 (20.00%)
    9 / 55 (16.36%)
         occurrences all number
    14
    12
    Oedema
         subjects affected / exposed
    11 / 60 (18.33%)
    10 / 55 (18.18%)
         occurrences all number
    12
    10
    Injection Site Reaction
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 55 (7.27%)
         occurrences all number
    3
    7
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 55 (3.64%)
         occurrences all number
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 55 (7.27%)
         occurrences all number
    8
    5
    Pulmonary Embolism
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 55 (5.45%)
         occurrences all number
    4
    3
    Dyspnoea
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 55 (3.64%)
         occurrences all number
    3
    3
    Epistaxis
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 55 (7.27%)
         occurrences all number
    3
    6
    Haemoptysis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Hiccups
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 55 (3.64%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    Agitation
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 60 (16.67%)
    8 / 55 (14.55%)
         occurrences all number
    12
    10
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    6 / 60 (10.00%)
    4 / 55 (7.27%)
         occurrences all number
    6
    5
    Weight decreased
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 55 (3.64%)
         occurrences all number
    2
    3
    C-reactive protein increased
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 55 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    14 / 60 (23.33%)
    9 / 55 (16.36%)
         occurrences all number
    21
    14
    Dizziness
         subjects affected / exposed
    8 / 60 (13.33%)
    1 / 55 (1.82%)
         occurrences all number
    11
    1
    Dysgeusia
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 55 (7.27%)
         occurrences all number
    6
    4
    Headache
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 55 (7.27%)
         occurrences all number
    6
    4
    Syncope
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    36 / 60 (60.00%)
    32 / 55 (58.18%)
         occurrences all number
    66
    54
    Leukopenia
         subjects affected / exposed
    29 / 60 (48.33%)
    29 / 55 (52.73%)
         occurrences all number
    90
    96
    Neutropenia
         subjects affected / exposed
    26 / 60 (43.33%)
    25 / 55 (45.45%)
         occurrences all number
    74
    66
    Thrombocytopenia
         subjects affected / exposed
    21 / 60 (35.00%)
    19 / 55 (34.55%)
         occurrences all number
    52
    45
    Lymphopenia
         subjects affected / exposed
    8 / 60 (13.33%)
    13 / 55 (23.64%)
         occurrences all number
    22
    35
    Thrombocytosis
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 55 (7.27%)
         occurrences all number
    2
    5
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 55 (9.09%)
         occurrences all number
    14
    7
    Deafness
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 55 (7.27%)
         occurrences all number
    5
    6
    Hypoacusis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 60 (61.67%)
    33 / 55 (60.00%)
         occurrences all number
    92
    70
    Constipation
         subjects affected / exposed
    25 / 60 (41.67%)
    13 / 55 (23.64%)
         occurrences all number
    48
    17
    Vomiting
         subjects affected / exposed
    21 / 60 (35.00%)
    19 / 55 (34.55%)
         occurrences all number
    53
    37
    Diarrhoea
         subjects affected / exposed
    9 / 60 (15.00%)
    9 / 55 (16.36%)
         occurrences all number
    17
    9
    Dyspepsia
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 55 (7.27%)
         occurrences all number
    4
    5
    Salivary hypersecretion
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 55 (0.00%)
         occurrences all number
    5
    0
    Stomatitis
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 55 (7.27%)
         occurrences all number
    3
    4
    Rectal haemorrhage
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    Dysphagia
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 55 (3.64%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    12 / 60 (20.00%)
    4 / 55 (7.27%)
         occurrences all number
    26
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 60 (13.33%)
    4 / 55 (7.27%)
         occurrences all number
    9
    4
    Dry skin
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 55 (9.09%)
         occurrences all number
    14
    8
    Pruritus
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 55 (10.91%)
         occurrences all number
    9
    6
    Skin exfoliation
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 55 (12.73%)
         occurrences all number
    10
    10
    Rash
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 55 (5.45%)
         occurrences all number
    7
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 55 (1.82%)
         occurrences all number
    5
    1
    Oliguria
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 55 (3.64%)
         occurrences all number
    6
    3
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 55 (7.27%)
         occurrences all number
    2
    4
    Infections and infestations
    Conjunctivitis allergic
         subjects affected / exposed
    13 / 60 (21.67%)
    11 / 55 (20.00%)
         occurrences all number
    27
    17
    Bronchitis
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 55 (0.00%)
         occurrences all number
    3
    0
    Candida infection
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 55 (1.82%)
         occurrences all number
    3
    1
    Lung infection
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 55 (7.27%)
         occurrences all number
    2
    4
    Respiratory tract infection
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 55 (1.82%)
         occurrences all number
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 60 (33.33%)
    14 / 55 (25.45%)
         occurrences all number
    43
    23
    Hypercreatininaemia
         subjects affected / exposed
    19 / 60 (31.67%)
    9 / 55 (16.36%)
         occurrences all number
    27
    12
    Hyperuricaemia
         subjects affected / exposed
    13 / 60 (21.67%)
    3 / 55 (5.45%)
         occurrences all number
    24
    3
    Hypocalcaemia
         subjects affected / exposed
    11 / 60 (18.33%)
    4 / 55 (7.27%)
         occurrences all number
    16
    5
    Hyperkalaemia
         subjects affected / exposed
    10 / 60 (16.67%)
    10 / 55 (18.18%)
         occurrences all number
    11
    17
    Hyponatraemia
         subjects affected / exposed
    10 / 60 (16.67%)
    8 / 55 (14.55%)
         occurrences all number
    15
    10
    Hypomagnesaemia
         subjects affected / exposed
    9 / 60 (15.00%)
    4 / 55 (7.27%)
         occurrences all number
    11
    5
    Hypokalaemia
         subjects affected / exposed
    7 / 60 (11.67%)
    3 / 55 (5.45%)
         occurrences all number
    15
    4
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 55 (3.64%)
         occurrences all number
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    6 / 55 (10.91%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2010
    One protocol amendmen was implemented (protocol NGR014-IPR/20B), by which the following changes of the original protocol NGR014-IPR/20A were made effective: - The order of administration of chemotherapies (cisplatin, gemcitabine, pemetrexed) was left at the Investigator’s discretion, according to the institutional clinical practice; - A blood sample performed at Day 8 for the assessment of haematology was added for patients on treatment with gemcitabine; - The possibility of administration of paracetamol by systemic route was added (in addition to oral route).

    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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