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    Clinical Trial Results:
    A two-part, multicentre, international phase I and II trial assessing the safety and efficacy of the Hsp90 inhibitor ganetespib in combination with paclitaxel weekly in women with high-grade serous, high-grade endometrioid, or undifferentiated, platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer

    Summary
    EudraCT number
    2013-003868-31
    Trial protocol
    AT   DE   BE  
    Global end of trial date
    04 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2019
    First version publication date
    28 Jun 2019
    Other versions
    Summary report(s)
    Summary GANNET53

    Trial information

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    Trial identification
    Sponsor protocol code
    GANNET53
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02012192
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical University of Innsbruck
    Sponsor organisation address
    Anichstraße 35, Innsbruck, Austria,
    Public contact
    Project Manager, AGO Studienzentrale, 0043 51250424132, ago.studienzentrale@i-med.ac.at
    Scientific contact
    Project Manager, AGO Studienzentrale, 0043 51250424132, ago.studienzentrale@i-med.ac.at
    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
    04 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to determine efficacy of ganetespib + paclitaxel weekly vs. paclitaxel weekly alone
    Protection of trial subjects
    • Adherence to good clinical practice (GCP) and applicable law • Definition of Inclusion/Exclusion criteria (the criteria were adapted during the conduct of the trial when new safety information was available) • Safety assessments consisted of monitoring and recording of adverse events (including serious adverse events); measurement of protocol-specified vital signs • Safety Data were evaluated regularly by the IDMC
    Background therapy
    -
    Evidence for comparator
    Paclitaxel, as being part of the taxane family of medication, was chosen as active comparator. Paclitaxel given as single agent on a weekly basis at a dose of 80-90 mg/m2/week, proved to be one of the most effective regimens in this situation, with response rates in the range of 20-60% (Lortholary et al, Ann Oncol 23:346-52, 2012; Richard et al, Nature Reviews Clinical Oncology 7:575-82, 2010). The combination of ganetespib and paclitaxel resulted in synergistic, anti-proliferative effects in vitro and in vivo. Concurrent treatment with both drugs resulted in a significant enhancement of antitumor activity compared to either agent alone (Proia et al, Invest New Drugs 6: 2210-9, 2012) Clinical evidence for the combination of a taxane and ganetespib was provided by trials which have evaluated the combination of docetaxol and ganetespib. As of 21 September 2015, 408 patients were treated with this combination. These trials have shown well tolerance, a lack of drug-drug interactions in phase I trials, a similar safety profile in phase IIb/III trials compared to single agent use and promising preliminary efficacy in patients with advanced adenocarcinoma of the lung.
    Actual start date of recruitment
    01 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 47
    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
    Recruitment period: Part II: 13.04.2015 - 21.09.2016

    Pre-assignment
    Screening details
    The following study screening assessments are to be completed within 4 weeks (28 days) prior to study entry. • Signed and dated informed consent • Verification of in- and exclusion criteria • High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer.

    Period 1
    Period 1 title
    Phase II: randomized, open-label,two-arm (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 P
    Arm description
    Patients received a standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause.
    Arm type
    Active comparator

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received a standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause.

    Arm title
    Arm P+G
    Arm description
    Patients received 150 mg/m2 ganetespib (dose established in Part I) in combination with the standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause. After at least six cycles of ganetespib combination therapy the physician was allowed to discontinue paclitaxel and to continue maintenance with ganetespib at the dose level previously used in the combination or re-escalated to the ganetespib dose level 0.
    Arm type
    Experimental

    Investigational medicinal product name
    Ganetespib
    Investigational medicinal product code
    PR2
    Other name
    STA-9090
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    150 mg/m2

    Number of subjects in period 1
    Arm P Arm P+G
    Started
    43
    90
    Completed
    43
    86
    Not completed
    0
    4
         Physician decision
    -
    3
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm P
    Reporting group description
    Patients received a standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause.

    Reporting group title
    Arm P+G
    Reporting group description
    Patients received 150 mg/m2 ganetespib (dose established in Part I) in combination with the standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause. After at least six cycles of ganetespib combination therapy the physician was allowed to discontinue paclitaxel and to continue maintenance with ganetespib at the dose level previously used in the combination or re-escalated to the ganetespib dose level 0.

    Reporting group values
    Arm P Arm P+G Total
    Number of subjects
    43 90 133
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    25 57 82
        From 65-84 years
    18 33 51
    Age continuous
    Units: years
        median (full range (min-max))
    62 (46 to 81) 61 (40 to 79) -
    Gender categorical
    Units: Subjects
        Female
    43 90 133
        Male
    0 0 0
    Subject analysis sets

    Subject analysis set title
    Arm P / Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety will include all patients who received at least one dose of study drug. In the safety analyses, patients will be included in the arm into which they have actually been randomized.

    Subject analysis set title
    Arm P / ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized patients. Analyses of this population assign patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Subject analysis set title
    Arm P / PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population includes all patients who received at least one dose of study treatment without major protocol deviations.

    Subject analysis set title
    Arm P+G / ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized patients. Analyses of this population assign patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Subject analysis set title
    Arm P+G / Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety will include all patients who received at least one dose of study drug. In the safety analyses, patients will be included in the arm into which they have actually been randomized.

    Subject analysis set title
    Arm P+G / PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population includes all patients who received at least one dose of study treatment without major protocol deviations.

    Subject analysis sets values
    Arm P / Safety Arm P / ITT Arm P / PP Arm P+G / ITT Arm P+G / Safety Arm P+G / PP
    Number of subjects
    43
    43
    42
    90
    90
    86
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    25
    25
    24
    57
    57
    54
        From 65-84 years
    18
    18
    18
    33
    33
    32
    Age continuous
    Units: years
        median (full range (min-max))
    62 (46 to 81)
    62 (46 to 81)
    62 (46 to 81)
    61 (40 to 79)
    61 (40 to 79)
    61 (40 to 79)
    Gender categorical
    Units: Subjects
        Female
    43
    43
    42
    90
    90
    86
        Male
    0
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Arm P
    Reporting group description
    Patients received a standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause.

    Reporting group title
    Arm P+G
    Reporting group description
    Patients received 150 mg/m2 ganetespib (dose established in Part I) in combination with the standard dose of 80 mg/m2 paclitaxel weekly. Patients received the therapy until disease progression or EoT due to any other cause. After at least six cycles of ganetespib combination therapy the physician was allowed to discontinue paclitaxel and to continue maintenance with ganetespib at the dose level previously used in the combination or re-escalated to the ganetespib dose level 0.

    Subject analysis set title
    Arm P / Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety will include all patients who received at least one dose of study drug. In the safety analyses, patients will be included in the arm into which they have actually been randomized.

    Subject analysis set title
    Arm P / ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized patients. Analyses of this population assign patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Subject analysis set title
    Arm P / PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population includes all patients who received at least one dose of study treatment without major protocol deviations.

    Subject analysis set title
    Arm P+G / ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population consists of all randomized patients. Analyses of this population assign patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Subject analysis set title
    Arm P+G / Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety will include all patients who received at least one dose of study drug. In the safety analyses, patients will be included in the arm into which they have actually been randomized.

    Subject analysis set title
    Arm P+G / PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PP population includes all patients who received at least one dose of study treatment without major protocol deviations.

    Primary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    PFS was defined as the days between randomization and the date of documented progression or death of any cause. For patients whose progression status could not be determined, their PFS data was censored at the last assessment date that the patient was confirmed to have no progression. Progression was evaluated according to RECIST 1.1 (therefore scans were performed of the chest (by X-ray or preferably by CT scan), abdomen and pelvis by CT scan (or MRI scans)) or by CA-125 as well as by the investigator on the basis of physical and/or gynecological examinations. Evidence of progressive disease was considered clear radiological, clinical, or symptomatic evidence. CA-125 evaluation alone was not defined as disease progression.
    End point type
    Primary
    End point timeframe
    Patients were assessed for disease response and progressive disease throughout the trial. Baseline assessment: 28 days before first dose of study drug Post baseline assessment: every 8 weeks (+/- 1 week) from date of randomization
    End point values
    Arm P Arm P+G Arm P / ITT Arm P / PP Arm P+G / ITT Arm P+G / PP
    Number of subjects analysed
    43
    90
    43
    42
    90
    86
    Units: Months
        median (confidence interval 95%)
    5.329 (4.006 to 6.652)
    3.454 (3.092 to 3.882)
    5.329 (4.006 to 6.652)
    5.329 (4.002 to 6.636)
    3.487 (3.092 to 3.882)
    3.454 (2.681 to 4.226)
    Statistical analysis title
    PFS in ITT population
    Comparison groups
    Arm P / ITT v Arm P+G / ITT
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.304
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.897
         upper limit
    1.895
    Statistical analysis title
    PFS in PP population
    Comparison groups
    Arm P / PP v Arm P+G / PP
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.136
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.911
         upper limit
    1.943

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    OS was defined as the days between randomization and the date of documented death from any cause. For patients whose survival status could not be determined, their OS data was censored at the last documented date that the patient is confirmed to be alive.
    End point type
    Secondary
    End point timeframe
    Survival status was observed throughout the study by regular visits of the patient. After the treatment period, the patient had regular long-term follow-ups in three-monthly intervals (+/- 14 days) where the survival status was recorded.
    End point values
    Arm P / ITT Arm P / PP Arm P+G / ITT Arm P+G / PP
    Number of subjects analysed
    43
    42
    90
    86
    Units: Months
        median (confidence interval 95%)
    14.901 (7.585 to 22.218)
    12.336 (5.274 to 19.397)
    10.954 (9.190 to 12.718)
    10.658 (8.690 to 12.626)
    Statistical analysis title
    OS in ITT population
    Comparison groups
    Arm P+G / ITT v Arm P / ITT
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.132
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.399
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.902
         upper limit
    2.171
    Statistical analysis title
    OS in PP population
    Comparison groups
    Arm P / PP v Arm P+G / PP
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.402
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.897
         upper limit
    2.192

    Secondary: Objective response rate (ORR)

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    End point title
    Objective response rate (ORR)
    End point description
    ORR was estimated as the proportion of responders, defined as a patient whose best overall response is partial response (PR) or complete response (CR) during the treatment period (best ORR). ORR was considered confirmed when the result was repeated in the following efficacy assessment, no less than four weeks later (confirmed ORR). Response was evaluated according to RECIST 1.1 (therefore scans were performed of the chest (by X-ray or preferably by CT scan), abdomen and pelvis by CT scan (or MRI scans)) or by CA-125 as well as by the investigator on the basis of physical and/or gynecological examinations. An objective response was confirmed by repeated assessment not earlier than 4 weeks after initial documentation (e.g. CA-125 measurement) or at the next scheduled tumor assessment if it was to occur more than 4 weeks after the initial response.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for disease response and progressive disease throughout the trial Baseline assessment: within a maximum of 28 days before first dose of study drug Post-baseline assessments: every 8 weeks (+/- 1 week) from date of randomization
    End point values
    Arm P / ITT Arm P / PP Arm P+G / ITT Arm P+G / PP
    Number of subjects analysed
    43
    42
    90
    86
    Units: Percentage of patients [%]
        Best objective response rate (best ORR)
    40
    38
    26
    26
        Confirmed best ORR
    28
    29
    14
    14
    Statistical analysis title
    Phase II: Best ORR in ITT
    Comparison groups
    Arm P / ITT v Arm P+G / ITT
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11
    Method
    Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Phase II: Best ORR in PP
    Comparison groups
    Arm P / PP v Arm P+G / PP
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.155
    Method
    Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Phase II: Confirmed best ORR in ITT
    Comparison groups
    Arm P / ITT v Arm P+G / ITT
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.394
    Method
    Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Phase II: Confirmed best ORR in PP
    Comparison groups
    Arm P / PP v Arm P+G / PP
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.38
    Method
    Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The safety was assessed for each patient at each patient contact throughout the trial.
    Adverse event reporting additional description
    Assessment started after informed consent had been obtained and events were reported until safety follow-up or EoT, event resolutaion to baseline, event was assessed as stable, patient is lost to FU or withdrew consent. Adverse Events (AEs) were measured according to NCI CTCAE version 4.03; laboratory parameters, ECOG PS and vital signs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm P+G
    Reporting group description
    -

    Reporting group title
    Arm P
    Reporting group description
    -

    Serious adverse events
    Arm P+G Arm P
    Total subjects affected by serious adverse events
         subjects affected / exposed
    62 / 86 (72.09%)
    18 / 43 (41.86%)
         number of deaths (all causes)
    64
    29
         number of deaths resulting from adverse events
    4
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemobilia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death NOS
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rupture of renal pelvis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Icterus
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (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
    Acute respiratory failure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Visual acuity reduced
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophagitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occlusive syndrome
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subobstruction colon
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal insufficiency
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erysipelas
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc prolapse
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection NOS
    Additional description: Reported Term: Infection back
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 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 P+G Arm P
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 86 (100.00%)
    41 / 43 (95.35%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Hot flashes
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Hypotension
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 43 (0.00%)
         occurrences all number
    6
    0
    Lymphoedema
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 43 (4.65%)
         occurrences all number
    5
    2
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 43 (6.98%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    22 / 86 (25.58%)
    11 / 43 (25.58%)
         occurrences all number
    34
    14
    Oedema limbs
         subjects affected / exposed
    7 / 86 (8.14%)
    4 / 43 (9.30%)
         occurrences all number
    7
    4
    Oedema peripheral
         subjects affected / exposed
    6 / 86 (6.98%)
    7 / 43 (16.28%)
         occurrences all number
    6
    7
    Fatigue
         subjects affected / exposed
    26 / 86 (30.23%)
    8 / 43 (18.60%)
         occurrences all number
    32
    9
    Fever
         subjects affected / exposed
    10 / 86 (11.63%)
    0 / 43 (0.00%)
         occurrences all number
    10
    0
    Malaise
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Mucosal inflammation
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 43 (0.00%)
         occurrences all number
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 86 (18.60%)
    4 / 43 (9.30%)
         occurrences all number
    16
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    13 / 86 (15.12%)
    0 / 43 (0.00%)
         occurrences all number
    29
    0
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 86 (10.47%)
    4 / 43 (9.30%)
         occurrences all number
    13
    9
    Neutrophil count decreased
         subjects affected / exposed
    26 / 86 (30.23%)
    10 / 43 (23.26%)
         occurrences all number
    45
    21
    Weight loss
         subjects affected / exposed
    9 / 86 (10.47%)
    0 / 43 (0.00%)
         occurrences all number
    10
    0
    White blood cell count decreased
         subjects affected / exposed
    13 / 86 (15.12%)
    6 / 43 (13.95%)
         occurrences all number
    20
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    56 / 86 (65.12%)
    27 / 43 (62.79%)
         occurrences all number
    89
    52
    Thrombocytopenia
         subjects affected / exposed
    7 / 86 (8.14%)
    0 / 43 (0.00%)
         occurrences all number
    8
    0
    Respiratory, thoracic and mediastinal disorders
    Common cold
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    5
    Cough
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 43 (6.98%)
         occurrences all number
    5
    3
    Dyspnoea
         subjects affected / exposed
    13 / 86 (15.12%)
    9 / 43 (20.93%)
         occurrences all number
    16
    12
    Epistaxis
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 43 (4.65%)
         occurrences all number
    5
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Dysgeusia
         subjects affected / exposed
    5 / 86 (5.81%)
    5 / 43 (11.63%)
         occurrences all number
    5
    5
    Headache
         subjects affected / exposed
    10 / 86 (11.63%)
    2 / 43 (4.65%)
         occurrences all number
    10
    2
    Neuropathy peripheral
         subjects affected / exposed
    35 / 86 (40.70%)
    21 / 43 (48.84%)
         occurrences all number
    42
    26
    Paresthesia
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    8 / 86 (9.30%)
    2 / 43 (4.65%)
         occurrences all number
    11
    2
    Abdominal pain
         subjects affected / exposed
    31 / 86 (36.05%)
    12 / 43 (27.91%)
         occurrences all number
    41
    13
    Constipation
         subjects affected / exposed
    21 / 86 (24.42%)
    9 / 43 (20.93%)
         occurrences all number
    32
    12
    Diarrhoea
         subjects affected / exposed
    73 / 86 (84.88%)
    15 / 43 (34.88%)
         occurrences all number
    405
    28
    Dry mouth
         subjects affected / exposed
    6 / 86 (6.98%)
    2 / 43 (4.65%)
         occurrences all number
    6
    2
    Dyspepsia
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 86 (6.98%)
    2 / 43 (4.65%)
         occurrences all number
    6
    2
    Mucositis oral
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 43 (0.00%)
         occurrences all number
    6
    0
    Nausea
         subjects affected / exposed
    41 / 86 (47.67%)
    21 / 43 (48.84%)
         occurrences all number
    97
    51
    Vomiting
         subjects affected / exposed
    29 / 86 (33.72%)
    9 / 43 (20.93%)
         occurrences all number
    56
    12
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    35 / 86 (40.70%)
    14 / 43 (32.56%)
         occurrences all number
    36
    14
    Dry skin
         subjects affected / exposed
    8 / 86 (9.30%)
    0 / 43 (0.00%)
         occurrences all number
    8
    0
    Erythema
         subjects affected / exposed
    0 / 86 (0.00%)
    5 / 43 (11.63%)
         occurrences all number
    0
    7
    Nail infection NOS
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 43 (4.65%)
         occurrences all number
    8
    2
    Rash
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 43 (9.30%)
         occurrences all number
    5
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 43 (4.65%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    9 / 86 (10.47%)
    4 / 43 (9.30%)
         occurrences all number
    11
    5
    Muscle spasms
         subjects affected / exposed
    11 / 86 (12.79%)
    2 / 43 (4.65%)
         occurrences all number
    13
    2
    Myalgia
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Pain in extremity
         subjects affected / exposed
    9 / 86 (10.47%)
    3 / 43 (6.98%)
         occurrences all number
    10
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    18 / 86 (20.93%)
    6 / 43 (13.95%)
         occurrences all number
    29
    6
    Hypokalaemia
         subjects affected / exposed
    7 / 86 (8.14%)
    3 / 43 (6.98%)
         occurrences all number
    7
    3
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 43 (0.00%)
         occurrences all number
    5
    0
    Urinary tract infection
         subjects affected / exposed
    8 / 86 (9.30%)
    6 / 43 (13.95%)
         occurrences all number
    11
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2014
    The protocol was amended to address the recommendations of the competent and ethical committees of the participating countries and the change in IMP labelling site from Landesapotheke Salzburg, Austria to Fisher Scientific Horsham, UK. (Protocol V1.5)
    10 Jun 2014
    The protocol was being amended to address the recommendations of the competent authority of France ANSM and a recommendation of the DSMC. The DSMC requests not to use bone marrow colony-stimulating factors during the DLT observation period in order not to bias the lasting of the neutropenia. The French competent authority ANSM requested restrictions in the cardiac monitoring procedure. (Protocol V1.6)
    06 Feb 2015
    The protocol was amended after the review of the Phase I DLT period data, to determine the safe dose of ganetespib to be used and to address the recommendations of the DSMC and agreements of the trial consortia. The entire document was changed to reflect the dosage of 150 mg/m² ganetespib to be used in Phase II of the GANNET53 protocol. Several chapters were changed according new information provided by the updated version of the Investigator’s Brochure Edition 10 from 26 November 2014 and updated safety information from the GALAXY-1 trial. An adjustment to the PK sampling time points was made to incorporate the administration of the premedication for paclitaxel in the sampling time scheme. (Protocol V1.7)
    11 Jan 2016
    The protocol was amended after a change in the safety evaluation of the IMP ganetespib, review of the Phase II safety data, and to address the recommendations of the DSMC. The in- and exclusion criteria were extended to reduce the risk/increase the safety for GIP in our patient cohort. An adjustment to the updated IB Version 11 was made to keep safety information up to date. Time points of PRO assessment during Long-term FU were adapted to meet the decision of the PRO Committee. (Protocol V1.8)
    18 Feb 2016
    The protocol was amended to address the requests from the BfArM to reflect the gastro-intestinal perforation in the summary of known and potential risks of ganetespib. (Protocol V1.9)

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Sep 2016
    The decision of the GANNET53 Steering Committee based on the recommendations of the DSMC and was taken primarily due to the decision of the company providing ganetespib to stop the production of ganetespib. As there were no proven significant unfavourable efficacy and safety concerns, the Steering Committee allowed screened and registered patients to be randomised. Patients who were on trial at the time of recruitment stop had to be informed by the investigator about the recruitment stop and the reasons for it and were allowed to continue the current treatment until progression, if the patient and their treating physician wished to do so.
    -

    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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