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    Clinical Trial Results:
    Phase II study in patient in first line for HER - metastasis breast cancer treated with eribulin and bevacizumab

    Summary
    EudraCT number
    		 2013-001710-15
    Trial protocol
    		 FR  
    Global end of trial date
    26 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Aug 2023
    First version publication date
    16 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GINECO-BR110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ARCAGY-GINECO
    Sponsor organisation address
    8 rue Lamennais , Paris, France, 75008
    Public contact
    MARMION, ARCAGY-GINECO, 33 1 42348323,
    Scientific contact
    MARMION, ARCAGY-GINECO, 33 1 42348323,
    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
    10 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the proportion of non-progressive patients at 1 year (disease control rate or non-progression rate at 12 months)
    Protection of trial subjects
    This study was conducted according to the recommendations then in effect: - the Huriet law (n°88-1138) of December 20, 1988 relating to the Protection of Persons taking part in Biomedical Research and amended by the public health law (n°2004-806) of August 9, 2004, - the Data Protection Act No. 78-17 amended by Law No. 2004-801 of August 6, 2004 on the protection of individuals with regard to the processing of personal data, - the Bioethics law n° 2004-800 of August 6, 2004, - good clinical practices from the international harmonization conference (ICH-E6 of 07/17/1996), - European direction (2001/20/EC) on the conduct of clinical trials. Before the start of the study, the protocol and the related documents (patient information, consent form, investigators brochure) were submitted for review by the National Agency for the Safety of Medicines and Health Products (ANSM ) and the Committee for the Protection of Persons (CPP) Ile de France 1. They obtained authorization from the ANSM on 07/19/2013 and the favorable opinion of the CPP Ile de France 1 on 06/11/2013.
    Background therapy
    		 The efficacy of eribulin is well established in patients with metastatic breast cancer previously treated with taxanes and anthracyclines. The Embrace study found a response rate of 12% in multi-treated patients refractory to the last line of chemotherapy. The benefit is comparable in patients refractory or not to taxanes, and pretreated or not with capecitabine. We can therefore expect a response rate at least equivalent in first-line metastatic treatment to that of taxanes or capecitabine. Phase II of eribulin (36) in first line goes in this direction because it highlights a response rate comparable to that found in first line. line with paclitaxel in the study by K Miller (32): 27.1% versus 21% with a strictly identical PFS. Adding bevacizumab to paclitaxel increased the response rate from 21% to 37% and the PFS from 5.9 to 11.8 months. The phase III chemotherapy combinations with bevacizumab all showed a benefit in favor of the combination in terms of response rate and PFS. Eribulin is a cytotoxic agent with a mode of action very similar to paclitaxel by inhibiting microtubules. We can expect its association with bevacizumab to increase its efficacy in terms of response rate and PFS in the same way as with all the other cytotoxic drugs studied and particularly paclitaxel. The toxicity profile of eribulin is very close to that of paclitaxel, essentially neuropathy and hematotoxicity, but phase II suggests a better therapeutic index with a lower rate of neuropathy (12.5% grade 3-4 versus 17% with paclitaxel).
    Evidence for comparator
    		 It therefore seems particularly interesting to study the efficacy and tolerance of the combination of eribulin and bevacizumab in first-line metastatic treatment in Her2-negative breast cancer. All the cytotoxic agents associated with bevacizumab in the various phase III were at their recommended dose in monotherapy and in particular the dose in the Marketing Authorization recommended for paclitaxel in combination with bevacizumab is that of monotherapy. This is justified by the absence of cross-toxicity between cytotoxics and bevacizumab. The ESMERALDA study will therefore focus on the combination of bevacizumab and eribulin, at the recommended doses as monotherapy, with dose reduction in the event of toxicity. In the paclitaxel bevacizumab combination, the disease control rate at one year is 50%, which will therefore be considered as a promising rate and the reference for the statistical calculation of the sample in our study.
    Actual start date of recruitment
    13 Nov 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    41
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 62 patients were enrolled between September 2013 and September 2014.

    Pre-assignment
    Screening details
    		 One patient withdrew consent before receiving treatment, therefore the intention-to-treat population included 61 treated patients.

    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
    		 Bevacizumab + Eribulin
    Arm description
    		 A total of 62 patients were enrolled. One patient withdrew consent before receiving treatment, therefore the intention-to-treat population included 61 treated patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg at D1 The cycles were repeated every 3 weeks (D1=D22). Bevacizumab treatment was continued until progression or intolerable toxicity.

    Investigational medicinal product name
    Eribuline
    Investigational medicinal product code
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1,23 mg/m2 at D1 and at D8 The cycles were repeated every 3 weeks (D1=D22). Eribulin treatment was administered for up to 6 cycles or until progression as long as the benefit/risk ratio was considered favorable for the patient.

    Number of subjects in period 1
    		Bevacizumab + Eribulin
    Started
    62
    Completed
    61
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 62 62
    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)
    		 41 41
        From 65-84 years
    		 21 21
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59 (38 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 62 62
    Histological grade at diagnosis
    Units: Subjects
        01
    		 6 6
        02
    		 31 31
        03
    		 21 21
        Unknown
    		 3 3
        Patient withdrawn consent
    		 1 1
    Prior chemotherapy
    Units: Subjects
        Neoadjuvant
    		 12 12
        Adjuvant
    		 31 31
        NA
    		 19 19
    Prior radiotherapy
    Units: Subjects
        Prior radiotherapy
    		 48 48
        NA
    		 14 14
    Prior endocrine therapy
    Units: Subjects
        For metastatic disease
    		 22 22
        Other
    		 18 18
        NA
    		 22 22
    ECOG performance status at inclusion
    Units: Subjects
        00
    		 35 35
        01
    		 25 25
        Unknown
    		 1 1
        Patient withdrawn consent
    		 1 1
    De novo metastatic disease
    Units: Subjects
        De novo metastatic disease
    		 13 13
        NA
    		 49 49
    Number of metastatic sites
    Units: Subjects
        01
    		 21 21
        02
    		 22 22
        ≥3
    		 18 18
        Patient withdrawn consent
    		 1 1
    Receptor status at diagnosis: Estrogen receptor positive
    Units: Subjects
        Estrogen receptor positive
    		 47 47
        NA
    		 15 15
    Receptor status at diagnosis: Progesterone receptor positive
    Units: Subjects
        Progesterone receptor positive
    		 34 34
        NA
    		 28 28
    Receptor status at diagnosis: Triple negative
    Units: Subjects
        Triple negative
    		 10 10
        NA
    		 52 52
    Metastatic sites: Liver
    Units: Subjects
        Liver
    		 25 25
        NA
    		 37 37
    Metastatic sites: Lung
    Units: Subjects
        Lung
    		 23 23
        NA
    		 39 39
    Metastatic sites: Pleura
    Units: Subjects
        Pleura
    		 5 5
        NA
    		 57 57
    Metastatic sites: Bone
    Units: Subjects
        Bone
    		 34 34
        NA
    		 28 28
    Metastatic sites: Lymph nodes
    Units: Subjects
        Lymph nodes
    		 21 21
        NA
    		 41 41
    Type of (neo)adjuvant chemotherapy: Paclitaxel
    Units: Subjects
        Paclitaxel
    		 4 4
        NA
    		 58 58
    Type of (neo)adjuvant chemotherapy: Docetaxel
    Units: Subjects
        Docetaxel
    		 30 30
        NA
    		 32 32
    Type of (neo)adjuvant chemotherapy: Anthracycline
    Units: Subjects
        Anthracycline
    		 38 38
        NA
    		 24 24
    Type of (neo)adjuvant chemotherapy: Cyclophosphamide
    Units: Subjects
        Cyclophosphamide
    		 39 39
        NA
    		 23 23
    Type of (neo)adjuvant chemotherapy: 5-FU
    Units: Subjects
        5-FU
    		 32 32
        NA
    		 30 30
    Histologic subtype at diagnosis: Ductal
    Units: Subjects
        Ductal
    		 54 54
        NA
    		 8 8
    Histologic subtype at diagnosis: Lobular
    Units: Subjects
        Lobular
    		 5 5
        NA
    		 57 57
    Histologic subtype at diagnosis: Mucinous
    Units: Subjects
        Mucinous
    		 1 1
        NA
    		 61 61
    Histologic subtype at diagnosis: Tubulo-lobular
    Units: Subjects
        Tubulo-lobular
    		 1 1
        NA
    		 61 61
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A total of 62 patients were recruited between September 2013 and September 2014. One patient withdrew consent prior to receiving treatment, therefore, the intent-to-treat population comprised 61 treated patients. Among these, one patient changed treatment before 12 months despite stable disease, thus the evaluable population for the primary endpoint comprised 60 patients.

    Subject analysis sets values
    		 ITT population
    Number of subjects
    61
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    41
        From 65-84 years
    21
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    59 (38 to 77)
    Gender categorical
    Units: Subjects
        Female
    61
    Histological grade at diagnosis
    Units: Subjects
        01
    6
        02
    31
        03
    21
        Unknown
    3
        Patient withdrawn consent
    1
    Prior chemotherapy
    Units: Subjects
        Neoadjuvant
    12
        Adjuvant
    31
        NA
    19
    Prior radiotherapy
    Units: Subjects
        Prior radiotherapy
    48
        NA
    14
    Prior endocrine therapy
    Units: Subjects
        For metastatic disease
    22
        Other
    18
        NA
    22
    ECOG performance status at inclusion
    Units: Subjects
        00
    35
        01
    25
        Unknown
    1
        Patient withdrawn consent
    1
    De novo metastatic disease
    Units: Subjects
        De novo metastatic disease
    13
        NA
    49
    Number of metastatic sites
    Units: Subjects
        01
    21
        02
    22
        ≥3
    18
        Patient withdrawn consent
    1
    Receptor status at diagnosis: Estrogen receptor positive
    Units: Subjects
        Estrogen receptor positive
    47
        NA
    15
    Receptor status at diagnosis: Progesterone receptor positive
    Units: Subjects
        Progesterone receptor positive
    34
        NA
    28
    Receptor status at diagnosis: Triple negative
    Units: Subjects
        Triple negative
    10
        NA
    52
    Metastatic sites: Liver
    Units: Subjects
        Liver
    25
        NA
    37
    Metastatic sites: Lung
    Units: Subjects
        Lung
    23
        NA
    39
    Metastatic sites: Pleura
    Units: Subjects
        Pleura
    5
        NA
    57
    Metastatic sites: Bone
    Units: Subjects
        Bone
    34
        NA
    28
    Metastatic sites: Lymph nodes
    Units: Subjects
        Lymph nodes
    21
        NA
    41
    Type of (neo)adjuvant chemotherapy: Paclitaxel
    Units: Subjects
        Paclitaxel
    4
        NA
    58
    Type of (neo)adjuvant chemotherapy: Docetaxel
    Units: Subjects
        Docetaxel
    30
        NA
    32
    Type of (neo)adjuvant chemotherapy: Anthracycline
    Units: Subjects
        Anthracycline
    38
        NA
    24
    Type of (neo)adjuvant chemotherapy: Cyclophosphamide
    Units: Subjects
        Cyclophosphamide
    39
        NA
    23
    Type of (neo)adjuvant chemotherapy: 5-FU
    Units: Subjects
        5-FU
    32
        NA
    30
    Histologic subtype at diagnosis: Ductal
    Units: Subjects
        Ductal
    54
        NA
    8
    Histologic subtype at diagnosis: Lobular
    Units: Subjects
        Lobular
    5
        NA
    57
    Histologic subtype at diagnosis: Mucinous
    Units: Subjects
        Mucinous
    1
        NA
    61
    Histologic subtype at diagnosis: Tubulo-lobular
    Units: Subjects
        Tubulo-lobular
    1
        NA
    61

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + Eribulin
    Reporting group description
    		 A total of 62 patients were enrolled. One patient withdrew consent before receiving treatment, therefore the intention-to-treat population included 61 treated patients.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    A total of 62 patients were recruited between September 2013 and September 2014. One patient withdrew consent prior to receiving treatment, therefore, the intent-to-treat population comprised 61 treated patients. Among these, one patient changed treatment before 12 months despite stable disease, thus the evaluable population for the primary endpoint comprised 60 patients.

    Primary: The 1-year non-progression rate

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    End point title
    		 The 1-year non-progression rate [1]
    End point description
    Based on a Simon's two stage design to detect with alpha =0.05 and a power of 80%, a PFS at 1-year rate of 50% (not reached). At the data cutoff, disease progression or death had been recorded in 58 (95%) of the 61 treated patients. The 1-year non-progression rate was 32% (95% confidence interval [CI]: 20-43%).
    End point type
    Primary
    End point timeframe
    Overall trial
    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: Trial's methodology is based on a Simon's two step design. Results are given with 95% Confidence Interval. This endpoint was chosen to provide a clear threshold rapidly and reliably in a single-arm study.
    End point values
    		 ITT population
    Number of subjects analysed
    61
    Units: percent
    number (confidence interval 95%)
        The 1-year non-progression rate (%)
    32 (20 to 43)
    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
    At the data cutoff, disease progression or death had been recorded in 58 (95%) of the 61 treated patients. The 1-year non-progression rate was 32% (95% confidence interval [CI]: 20-43%). The ORR in 59 evaluable patients was 47% (95% CI: 34-60%), including complete response in six patients (10%). Median PFS was 8.3 months (95% CI: 7.0-9.6 months)
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 ITT population
    Number of subjects analysed
    61
    Units: month
    median (confidence interval 95%)
        Progression-free survival (PFS)
    8.3 (7.0 to 9.6)
    Attachments
    		 Untitled (Filename: Figure 1 - Progression-free survival.JPG)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 ITT population
    Number of subjects analysed
    61
    Units: month
    median (confidence interval 95%)
        Overall survival (OS)
    28.3 (22.8 to 33.9)
    Attachments
    		 Figure 2 - Overall survival (OS)
    No statistical analyses for this end point

    Secondary: Baseline visual analog scale (VAS) score

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    End point title
    		 Baseline visual analog scale (VAS) score
    End point description
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Bevacizumab + Eribulin
    Number of subjects analysed
    62
    Units: number
    arithmetic mean (standard deviation)
        Visual analog scale (VAS) score
    6.55 ± 2.20
    No statistical analyses for this end point

    Secondary: Cycle 4 visual analog scale (VAS) score

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    End point title
    		 Cycle 4 visual analog scale (VAS) score
    End point description
    A baseline VAS score was available in 60 of the 62 patients enrolled. The mean score was 6.55 (standard deviation [SD] 2.20). At cycle 4, 38 patients reported a VAS score. The mean score at cycle 4 was 6.66 (SD 2.16), showing no deterioration of quality of life with treatment.
    End point type
    Secondary
    End point timeframe
    Overall trial
    End point values
    		 Bevacizumab + Eribulin
    Number of subjects analysed
    38
    Units: number
    arithmetic mean (standard deviation)
        Cycle 4 VAS score
    6.66 ± 2.16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    ITT population
    Reporting group description
    		 -

    Serious adverse events
    		 ITT population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 61 (47.54%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Radiomucositis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertention
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences causally related to treatment / all
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    Arterial hypertention
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Leg vein thrombosis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Appendectomy
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile aplasia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right arm and breast pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Aspecific colitis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Sub acute pulmonary edema
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Left ankle ulcer
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteo-chemo necrosis of the jaw
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Septicemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious syndrome with no obvious point of appeal
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ITT population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 61 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    50 / 61 (81.97%)
         occurrences all number
    50
    Edema
         subjects affected / exposed
    13 / 61 (21.31%)
         occurrences all number
    13
    Arterial ischemia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    47 / 61 (77.05%)
         occurrences all number
    47
    Fatigue
         subjects affected / exposed
    45 / 61 (73.77%)
         occurrences all number
    45
    Headache
         subjects affected / exposed
    18 / 61 (29.51%)
         occurrences all number
    18
    Fever
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    9
    Dysphonia
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    8
    Cough
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    12 / 61 (19.67%)
         occurrences all number
    12
    Rhinitis
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Product issues
    Mucositis
         subjects affected / exposed
    16 / 61 (26.23%)
         occurrences all number
    16
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Myocardial infarction
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Left ventricular ejection fraction (LVEF) decreased
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Nervous system disorders
    Paresthesia/dysesthesia
         subjects affected / exposed
    26 / 61 (42.62%)
         occurrences all number
    26
    Peripheral motor neuropathy
         subjects affected / exposed
    15 / 61 (24.59%)
         occurrences all number
    15
    Blood and lymphatic system disorders
    Leukocytopenia
         subjects affected / exposed
    44 / 61 (72.13%)
         occurrences all number
    44
    Neutropenia
         subjects affected / exposed
    43 / 61 (70.49%)
         occurrences all number
    43
    Lymphocytopenia
         subjects affected / exposed
    28 / 61 (45.90%)
         occurrences all number
    28
    Anemia
         subjects affected / exposed
    26 / 61 (42.62%)
         occurrences all number
    26
    Febrile neutropenia
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    3
    Hemorrhage
         subjects affected / exposed
    22 / 61 (36.07%)
         occurrences all number
    22
    Thrombosis
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 61 (37.70%)
         occurrences all number
    23
    Constipation
         subjects affected / exposed
    23 / 61 (37.70%)
         occurrences all number
    23
    Diarrhea
         subjects affected / exposed
    21 / 61 (34.43%)
         occurrences all number
    21
    Vomiting
         subjects affected / exposed
    12 / 61 (19.67%)
         occurrences all number
    12
    Dysphagia
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    3
    Appendicitis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Colitis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Hepatobiliary disorders
    GGT increased
         subjects affected / exposed
    19 / 61 (31.15%)
         occurrences all number
    19
    Transaminase increased
         subjects affected / exposed
    15 / 61 (24.59%)
         occurrences all number
    15
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    34 / 61 (55.74%)
         occurrences all number
    34
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 61 (19.67%)
         occurrences all number
    12
    Myalgia
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    9
    Cramp
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Osteonecrosis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Infections and infestations
    Urinary infection
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    8
    Rhinopharyngitis
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Septicemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    8
    Weight loss
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    8
    Dysgeusia
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2013
    Amendement 1

    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.
    It's a single-arm design with no standard comparator Lack of detailed information on the evolution/resolution of neuropathy over time, the heterogeneity of the patient population, and the relevance of this regimen in the context of emerging options

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33188992
    For support, Contact us.
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