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    Clinical Trial Results:
    NGR018: Randomized phase II study of NGR-hTNF plus pegylated liposomal doxorubicin (PLD) versus PLD in platinum-resistant ovarian cancer

    Summary
    EudraCT number
    		 2010-023613-61
    Trial protocol
    		 IT   GB  
    Global end of trial date
    23 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2020
    First version publication date
    01 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NGR018
    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 Development , MolMed S.p.A. , 0039 0221277234, clinical.operations@molmed.com
    Scientific contact
    Clinical Development , MolMed S.p.A. , 0039 0221277234, 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
    25 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare progression-free survival (PFS) in patients randomized to NGR-hTNF plus PLD versus patients randomized to PLD
    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
    		 Patients previously treated with a maximum of two platinum-based regimen (cisplatin or carboplatin) plus paclitaxel and with documented progressive disease on treatment (refractory patient population) or within 6 months from last chemotherapy cycle (resistant patient population).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Italy: 120
    Worldwide total number of subjects
    133
    EEA total number of subjects
    133
    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)
    82
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study period: First patient enrolled: 18 July 2011; Last patient completed: 27 January 2016; End of study: 23 December 2016; 8 investigational study sites (6 sites in Italy and 2 sites in United Kingdom)

    Pre-assignment
    Screening details
    		 Totally 133 consented and screened patients were randomly assigned to the treatment group through a centralized randomization system using the following stratification factors: primary platinum resistance or acquired platinum resistance, type of anthracycline.

    Period 1
    Period 1 title
    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: NGR-hTNF plus an anthracycline
    Arm description
    		 Arm A (experimental arm = NGR-hTNF + anthracycline) -NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 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
    NGR-hTNF: 0.8 ug/m² as 60-minute intravenous (iv) infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR NGR-hTNF: 0.8 ug/m² as 60-minute iv infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Anthracycline
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NGR-hTNF: 0.8 ug/m² as 60-minute intravenous (iv) infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR NGR-hTNF: 0.8 ug/m² as 60-minute iv infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Anthracycline
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NGR-hTNF: 0.8 ug/m² as 60-minute intravenous (iv) infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR NGR-hTNF: 0.8 ug/m² as 60-minute iv infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Arm title
    		 Arm B: anthracycline alone
    Arm description
    		 Arm B (control arm = anthracycline) - Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated liposomal doxorubicin
    Investigational medicinal product code
    Other name
    Anthracycline
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    - Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Anthracycline
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    - Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Number of subjects in period 1
    		Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Started
    68
    65
    Completed
    52
    49
    Not completed
    16
    16
         Physician decision
    11
    10
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    3
    1
         Death
    2
    -
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: NGR-hTNF plus an anthracycline
    Reporting group description
    		 Arm A (experimental arm = NGR-hTNF + anthracycline) -NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Reporting group title
    Arm B: anthracycline alone
    Reporting group description
    		 Arm B (control arm = anthracycline) - Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Reporting group values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone Total
    Number of subjects
    		 68 65 133
    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 40 82
        From 65-84 years
    		 26 25 51
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 60.28 ± 9.77 60.22 ± 9.17 -
    Gender categorical
    Units: Subjects
        Female
    		 68 65 133
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm A: NGR-hTNF plus an anthracycline
    Reporting group description
    		 Arm A (experimental arm = NGR-hTNF + anthracycline) -NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - NGR-hTNF: 0.8 ug/m² as 60-minute intravenous infusion every week until confirmed evidence of disease progression, plus Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Reporting group title
    Arm B: anthracycline alone
    Reporting group description
    		 Arm B (control arm = anthracycline) - Pegylated liposomal doxorubicin: 50 mg/m2 iv every 4 weeks until confirmed evidence of disease progression OR - Doxorubicin: 60 mg/m2 iv every 3 weeks for a maximum of 8 cycles

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Progression-free survival (PFS), defined as the time from the date of randomization until disease progression, or death due to any cause.
    End point type
    Primary
    End point timeframe
    Progression-free survival (PFS) was measured after documented progressive disease (PD), specifically every 12 weeks.
    End point values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Number of subjects analysed
    68
    65
    Units: Days
        median (confidence interval 95%)
    87 (63 to 111)
    116 (61 to 158)
    Statistical analysis title
    		 Progression-free survival (PFS)
    Statistical analysis description
    The median PFS was 87 days (95% CI: 63-111 days) in arm A and 116 days (95% CI: 61-158 days) in arm B. Four (5.9%) patients in arm A and 9 (13.8%) in arm B were censored, while events (i.e. failures) were reported in 64 (94.1%) patients in arm A and in 56 (86.2%) in arm B. The comparison between arms in the log rank test did not show statistically significant differences (p = 0.232).
    Comparison groups
    Arm A: NGR-hTNF plus an anthracycline v Arm B: anthracycline alone
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.232
    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 type
    Secondary
    End point timeframe
    Progression-free survival (PFS) was measured after documented progressive disease (PD), specifically every 12 weeks.
    End point values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Number of subjects analysed
    68
    65
    Units: Days
        median (confidence interval 95%)
    322 (167 to 406)
    280 (236 to 304)
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    The median OS was 322 days (95% CI: 167-406 days) in arm A and 280 days (95% CI: 236-304 days) in arm B. Three (4.4%) patients in arm A and 10 (15.4%) in arm B were censored, while events (i.e. deaths) were reported in 65 (95.6%) patients in arm A and in 55 (84.6%) in arm B. The comparison between arms in the log rank test did not show statistically significant differences (p = 0.98).
    Comparison groups
    Arm A: NGR-hTNF plus an anthracycline v Arm B: anthracycline alone
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.98
    Method
    		 Logrank
    Confidence interval

    Secondary: Response rate (RR)

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    End point title
    		 Response rate (RR)
    End point description
    Response rate (RR), defined as the percentage of patients who had a best-response rating of complete or partial response, according to standard RECIST criteria;
    End point type
    Secondary
    End point timeframe
    Response rate was measured during the whole study and at each cycle.
    End point values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Number of subjects analysed
    68
    65
    Units: Percentage of patients
        number (confidence interval 95%)
    4.4 (0.9 to 12.4)
    6.2 (1.7 to 15.0)
    Statistical analysis title
    		 Response rate (RR)
    Statistical analysis description
    Overall, response to treatment (CR or PR) was reported in 3 (4.4%; 95% CI: 0.9-12.4 %) patients in arm A and in 4 (6.2%; 95% CI: 1.7-15.0 %) in arm B. The difference between arms was not statistically significant (p = 0.6529).
    Comparison groups
    Arm A: NGR-hTNF plus an anthracycline v Arm B: anthracycline alone
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6529
    Method
    		 Logrank
    Confidence interval

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    Disease Control Rate (overall/at each cycle) is defined as the percentage of subjects who have a Complete Response, a Partial Response or a Stable Disease(during the whole study/at each cycle).
    End point type
    Secondary
    End point timeframe
    Disease control rate (DCR) was measured during the whole study/at each cycle.
    End point values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Number of subjects analysed
    68
    65
    Units: Percentage of patients
        number (confidence interval 95%)
    55.9 (43.3 to 67.9)
    53.8 (41.0 to 66.3)
    Statistical analysis title
    		 Disease Control Rate
    Statistical analysis description
    Disease control (CR, PR or stable disease) was reported in 38 (55.9%; 95% CI: 43.3-67.9 %) patients in arm A and in 35 (53.8%; 95% CI: 41.0-66.3 %) in arm B. The difference between arms was not statistically significant (p = 0.8135). There were no statistically significant differences between arms in disease control rate at any treatment cycle.
    Comparison groups
    Arm B: anthracycline alone v Arm A: NGR-hTNF plus an anthracycline
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8135
    Method
    		 Logrank
    Confidence interval

    Secondary: Duration of disease control (DDC)

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    End point title
    		 Duration of disease control (DDC)
    End point description
    Duration of disease control: 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.
    End point type
    Secondary
    End point timeframe
    Duration of disease control was measured from the date of randomization until disease progression.
    End point values
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Number of subjects analysed
    68
    65
    Units: Days
        median (confidence interval 95%)
    144 (96 to 190)
    120 (94 to 191)
    Statistical analysis title
    		 Disease control rate (DDR)
    Statistical analysis description
    The median duration of disease control was 144 days (95% CI: 96-190 days) in arm A and 120 days (95% CI: 94-191 days) in arm B. One (2.6%) patient in arm A and 3 (8.6%) patients in arm B were censored, while events (i.e. failure of disease control) were reported in 37 (97.4%) patients in arm A and in 32 (91.4%) in arm B. The comparison between arms in the log rank test did not show statistically significant differences (p = 0.755).
    Comparison groups
    Arm A: NGR-hTNF plus an anthracycline v Arm B: anthracycline alone
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.755
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Unrelated events to be followed for 28 days after completion of the last treatment administration; related serious adverse events to be followed indefinitely until resolution or stabilization.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Arm A: NGR-hTNF plus an anthracycline
    Reporting group description
    		 -

    Reporting group title
    Arm B: anthracycline alone
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 68 (35.29%)
    19 / 65 (29.23%)
         number of deaths (all causes)
    65
    55
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Body Temperature
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Left Ventricular Failure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired self-care
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         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
    6 / 68 (8.82%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    7 / 7
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice Cholestatic
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (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
    3 / 68 (4.41%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obliterative Bronchiolitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Fungal Infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: NGR-hTNF plus an anthracycline Arm B: anthracycline alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 68 (98.53%)
    63 / 65 (96.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 65 (4.62%)
         occurrences all number
    7
    4
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    31 / 68 (45.59%)
    28 / 65 (43.08%)
         occurrences all number
    71
    39
    Fatigue
         subjects affected / exposed
    30 / 68 (44.12%)
    33 / 65 (50.77%)
         occurrences all number
    50
    43
    Pyrexia
         subjects affected / exposed
    17 / 68 (25.00%)
    12 / 65 (18.46%)
         occurrences all number
    25
    14
    Chills
         subjects affected / exposed
    10 / 68 (14.71%)
    1 / 65 (1.54%)
         occurrences all number
    13
    1
    Mucosal Inflammation
         subjects affected / exposed
    9 / 68 (13.24%)
    6 / 65 (9.23%)
         occurrences all number
    11
    7
    Oedema
         subjects affected / exposed
    5 / 68 (7.35%)
    6 / 65 (9.23%)
         occurrences all number
    5
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 68 (11.76%)
    9 / 65 (13.85%)
         occurrences all number
    9
    10
    Cough
         subjects affected / exposed
    6 / 68 (8.82%)
    9 / 65 (13.85%)
         occurrences all number
    6
    9
    Pulmonary Embolism
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 65 (1.54%)
         occurrences all number
    5
    1
    Pleural Effusion
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 65 (6.15%)
         occurrences all number
    3
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 65 (4.62%)
         occurrences all number
    7
    3
    Investigations
    Weight Decreased
         subjects affected / exposed
    6 / 68 (8.82%)
    6 / 65 (9.23%)
         occurrences all number
    6
    7
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 65 (3.08%)
         occurrences all number
    6
    2
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 65 (1.54%)
         occurrences all number
    5
    1
    Troponin Increased
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 65 (1.54%)
         occurrences all number
    3
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 65 (3.08%)
         occurrences all number
    4
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 68 (11.76%)
    3 / 65 (4.62%)
         occurrences all number
    14
    3
    Neuropathy Peripheral
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 65 (6.15%)
         occurrences all number
    7
    4
    Dysgeusia
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 65 (3.08%)
         occurrences all number
    5
    2
    Dizziness
         subjects affected / exposed
    3 / 68 (4.41%)
    3 / 65 (4.62%)
         occurrences all number
    4
    3
    Lethargy
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 65 (6.15%)
         occurrences all number
    4
    5
    Neurotoxicity
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 65 (6.15%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    51 / 68 (75.00%)
    39 / 65 (60.00%)
         occurrences all number
    123
    113
    Leukopenia
         subjects affected / exposed
    48 / 68 (70.59%)
    41 / 65 (63.08%)
         occurrences all number
    107
    115
    Anaemia
         subjects affected / exposed
    43 / 68 (63.24%)
    44 / 65 (67.69%)
         occurrences all number
    60
    77
    Thrombocytopenia
         subjects affected / exposed
    15 / 68 (22.06%)
    18 / 65 (27.69%)
         occurrences all number
    29
    47
    Lymphopenia
         subjects affected / exposed
    13 / 68 (19.12%)
    8 / 65 (12.31%)
         occurrences all number
    16
    12
    Febrile Neutropenia
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 65 (4.62%)
         occurrences all number
    5
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    32 / 68 (47.06%)
    30 / 65 (46.15%)
         occurrences all number
    54
    42
    Constipation
         subjects affected / exposed
    23 / 68 (33.82%)
    19 / 65 (29.23%)
         occurrences all number
    41
    20
    Vomiting
         subjects affected / exposed
    23 / 68 (33.82%)
    22 / 65 (33.85%)
         occurrences all number
    41
    32
    Diarrhoea
         subjects affected / exposed
    13 / 68 (19.12%)
    9 / 65 (13.85%)
         occurrences all number
    20
    10
    Stomatitis
         subjects affected / exposed
    11 / 68 (16.18%)
    9 / 65 (13.85%)
         occurrences all number
    12
    14
    Intestinal Obstruction
         subjects affected / exposed
    9 / 68 (13.24%)
    5 / 65 (7.69%)
         occurrences all number
    10
    7
    Ascites
         subjects affected / exposed
    4 / 68 (5.88%)
    6 / 65 (9.23%)
         occurrences all number
    4
    7
    Dyspepsia
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 65 (1.54%)
         occurrences all number
    3
    1
    Abdominal Discomfort
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 65 (4.62%)
         occurrences all number
    2
    3
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 65 (0.00%)
         occurrences all number
    10
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 68 (13.24%)
    10 / 65 (15.38%)
         occurrences all number
    11
    11
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    9 / 68 (13.24%)
    8 / 65 (12.31%)
         occurrences all number
    16
    11
    Erythema
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 65 (6.15%)
         occurrences all number
    3
    5
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 65 (6.15%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 65 (1.54%)
         occurrences all number
    9
    6
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 65 (4.62%)
         occurrences all number
    2
    3
    Urinary Tract Infection
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 65 (4.62%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    14 / 68 (20.59%)
    9 / 65 (13.85%)
         occurrences all number
    19
    10
    Hypokalaemia
         subjects affected / exposed
    5 / 68 (7.35%)
    7 / 65 (10.77%)
         occurrences all number
    6
    12
    Dehydration
         subjects affected / exposed
    4 / 68 (5.88%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    Hypercreatininaemia
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 65 (3.08%)
         occurrences all number
    4
    2
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    Hyponatraemia
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 65 (6.15%)
         occurrences all number
    3
    4
    Hypocalcaemia
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 65 (3.08%)
         occurrences all number
    2
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 65 (4.62%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2011
    Summary of changes: The primary objective of the study was modified from the documentation of the preliminary antitumor activity to the comparison of the PFS in the two treatment arms. The rapid reporting, monitoring and analysis of all SSEs occurring during the first two treatment cycles of the first 24 patients randomized in both arms and treated with PLD was added. The parameters of the statistical analysis as a result of the modification of the primary objective were modified. The criteria of evaluation of adverse events were modified to specify the relation to PLD.
    15 Mar 2011
    Summary of changes: The dose of PLD to be administered was modified from 40 mg/m2 to 50 mg/m2 and the rationale was modified accordingly.
    18 Nov 2011
    Summary of changes: the possibility to administer doxorubicin as an alternative to the PLD was included and the title of the protocol was modified accordingly. The rationale and the primary objective of the study were modified in agreement to the inclusion of doxorubicin as an alternative to PLD. The trial design as the doxorubicin was administered every 3 weeks while PLD every 4 weeks was modified. The exclusion criterion No. 2 was modified as patients who had already received previous treatment with anthracycline were not eligible. The treatment duration was updated as doxorubicin was administered for a maximum of 8 cycles. The reference to management of allergic hypersensitivity reaction related to NGR-hTNF was included. The type of anthracycline as stratification factor was added. It was specified that the SSEs to be reported were those occurred in PLD-treated patients. The criteria of evaluation for the adverse events to specify the relation to the anthracycline and not just to PLD were specified. The guidelines regarding dose modification of doxorubicin for hematologic and nonhematologic toxicity were included.
    16 Oct 2012
    Summary of changes: an additional cohort of 24 patients to be included in the study was added. The study design was modified as the additional cohort of patients received NGR-hTNF every week instead of once every 3 weeks, and the rationale of the study in agreement to the inclusion of an additional cohort of patients was modified accordingly. Please note that Protocol IPR/24.E has been re-labelled as protocol IPR/26.A for Italy only.

    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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