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    Clinical Trial Results:
    NGR012: A phase II study of NGR-hTNF administered in combination with doxorubicin every 3 weeks in patients affected by advanced or metastatic ovarian cancer

    Summary
    EudraCT number
    2007-000004-33
    Trial protocol
    IT  
    Global end of trial date
    17 Dec 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NGR012
    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
    MolMed S.p.A., Clinical Development, 0039 0221277234, clinical.operations@molmed.com
    Scientific contact
    MolMed S.p.A., Clinical Development, 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
    12 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Antitumor activity defined as response rate according to RECIST criteria
    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 affected by advanced or metastatic ovarian cancer previously treated with platinum regimens (cis or carboplatin) plus paclitaxel and with documented progression disease within 6 months from last chemotherapy administered (refractory/resistant population) or in progression disease after 6 months from last chemotherapy (platinum regimens plus paclitaxel) administered.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 2008
    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: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    17
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study period: First patient enrolled: 01 December 2008; Last patient completed: 17 December 2015; Study centres: 2 investigational study sites in Italy.

    Pre-assignment
    Screening details
    Totally 37 consented and screened patients received at least one dose of study medication and were included in the Safety population (SAF set).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    NGR-hTNF + doxorubicin
    Arm description
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.
    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
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.

    Number of subjects in period 1
    NGR-hTNF + doxorubicin
    Started
    37
    Completed
    26
    Not completed
    11
         Physician decision
    2
         Adverse event, non-fatal
    1
         Consent withdrawn by subject
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NGR-hTNF + doxorubicin
    Reporting group description
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.

    Reporting group values
    NGR-hTNF + doxorubicin Total
    Number of subjects
    37 37
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    17 17
        From 65-84 years
    20 20
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    57.0 (35 to 72) -
    Gender categorical
    Units: Subjects
        Female
    37 37
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    NGR-hTNF + doxorubicin
    Reporting group description
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.

    Primary: Response rate (RR)

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    End point title
    Response rate (RR) [1]
    End point description
    The primary endpoint of the study was antitumor activity defined as response rate according to RECIST criteria. Response rate was defined as the percentage of patients having as best response throughout the study a CR or a PR: (CR + PR)/n. of patients in ENR population.
    End point type
    Primary
    End point timeframe
    The response rate was measured during the whole study.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was conducted using Simon’s two-stage design method for the primary efficacy end point. Since 7 responses (complete or partial) were observed among the 37 patients, the study was to be considered to have a positive result.
    End point values
    NGR-hTNF + doxorubicin
    Number of subjects analysed
    37
    Units: Percentage of patients
        number (confidence interval 95%)
    18.9 (8.0 to 35.2)
    No statistical analyses for this end point

    Secondary: 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 baseline CT-scan date until the first observation of disease progression, or death due to any cause, or the last date the patient was known to be progression free or alive.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) was measured during the whole study/at each cycle.
    End point values
    NGR-hTNF + doxorubicin
    Number of subjects analysed
    37
    Units: months
        median (confidence interval 95%)
    4.7 (3.1 to 6.3)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall Survival (OS), defined as the time from baseline until the date of death from any cause or the last date the patient was known to be alive.
    End point type
    Secondary
    End point timeframe
    Patiens were followed for survival after documented disease progression or after discontinuation before disease progression (every 12 weeks)
    End point values
    NGR-hTNF + doxorubicin
    Number of subjects analysed
    37
    Units: Months
        median (confidence interval 95%)
    13.9 (9.3 to 17.3)
    No statistical analyses for this end point

    Secondary: Tumor marker CA125 detection

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    End point title
    Tumor marker CA125 detection
    End point description
    Changes from baseline of tumor marker CA125.
    End point type
    Secondary
    End point timeframe
    The level of tumor marker CA125 was measured before the treatment (within 14 days prior treatment) and during the treatment (every 2 cycles).
    End point values
    NGR-hTNF + doxorubicin
    Number of subjects analysed
    37
    Units: U/ml
        median (full range (min-max))
    1.8 (-1833.8 to 745.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events and serious adverse events occurring after initiation of trial treatment will be recorded for 28 days after completion of the last treatment cycle. All serious adverse events related to the study drug will be recorded indefinitely.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    NGR-hTNF + doxorubicin
    Reporting group description
    Patients received 60 minutes intravenous NGR-hTNF infusion every 3 weeks at dose of 0.8 μg/m2 before of a dose of doxorubicin 60 mg/m2 as 15 minutes infusion. At reaching of a cumulative dose of doxorubicin of 550 mg/m2, a continuation of treatment (if patient was showing an objective response or is in stable disease) with single agent NGR-hTNF at dose of 0.8 μg/m2 every 3 weeks was allowed.

    Serious adverse events
    NGR-hTNF + doxorubicin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 37 (18.92%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Infusion Site Extravasation
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    NGR-hTNF + doxorubicin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 37 (100.00%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    4
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Immune system disorders
    Contrast Media Allergy
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    31 / 37 (83.78%)
         occurrences all number
    84
    Anaemia
         subjects affected / exposed
    29 / 37 (78.38%)
         occurrences all number
    34
    Neutropenia
         subjects affected / exposed
    29 / 37 (78.38%)
         occurrences all number
    73
    Thrombocytosis
         subjects affected / exposed
    8 / 37 (21.62%)
         occurrences all number
    8
    Thrombocytopenia
         subjects affected / exposed
    5 / 37 (13.51%)
         occurrences all number
    8
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    15 / 37 (40.54%)
         occurrences all number
    18
    Headache
         subjects affected / exposed
    8 / 37 (21.62%)
         occurrences all number
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    33 / 37 (89.19%)
         occurrences all number
    37
    Chills
         subjects affected / exposed
    24 / 37 (64.86%)
         occurrences all number
    40
    Pyrexia
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    29 / 37 (78.38%)
         occurrences all number
    45
    Vomiting
         subjects affected / exposed
    24 / 37 (64.86%)
         occurrences all number
    43
    Constipation
         subjects affected / exposed
    23 / 37 (62.16%)
         occurrences all number
    32
    Stomatitis
         subjects affected / exposed
    19 / 37 (51.35%)
         occurrences all number
    19
    Diarrhoea
         subjects affected / exposed
    7 / 37 (18.92%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Hypocalcaemia
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Herpes Zoster
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2008
    Summary of changes: - The reference name of the sponsor was changed; - The introduction was modified according to the availability of results of new studies; - The production process of the study drug has been changed, and therefore the protocol has been modified for the sections regarding pharmaceutical form, labelling, mode of dispensing and returning, and other details on study drug; - Plan of visits schedule of assessments has been changed; - Criteria for evaluation of relationship of adverse events have been modified; - Other minor changes.

    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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