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    Clinical Trial Results:
    Randomized open label study to compare the efficacy and safety of everolimus followed by chemotherapy with STZ-5FU upon progression or the reverse sequence, chemotherapy with STZ-5FU followed by everolimus upon progression, in advanced progressive pNETs (SEQTOR study)

    Summary
    EudraCT number
    		 2013-000726-66
    Trial protocol
    		 SE   DE   IT   ES   DK   NL   FR   GB  
    Global end of trial date
    12 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2025
    First version publication date
    12 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GETNE1206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02246127
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE)
    Sponsor organisation address
    Velazquez St, 7-3o, Madrid, Spain,
    Public contact
    Trial Lead Coordinator, Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE), 34 934344412, getne@getne.org
    Scientific contact
    Trial Lead Coordinator, Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE), 34 934344412, getne@getne.org
    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
    08 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of the combination STZ-5FU chemotherapy followed by Everolimus 10 mg/day upon progression versus the reverse sequence in the treatment of advanced pancreatic neuroendocrine tumours (pNET), in terms of rate of patients with second progression free survival at 84 weeks of treatment, assessed by local investigator using RECIST criteria 1.0.
    Protection of trial subjects
    This assignment will designate the user as the primary user for the listed clinical trial in regards to result related information. It will enable them to prepare and post result related information for this trials on behalf of the sponsor in accordance with Commission Guideline 2012/C 302/03 and its technical guidance on the format of the data fields of result-related information on clinical trials submitted in accordance with article 57(2) of Regulation (EC) No 726/2004 and article 41(2) of Regulation (EC) No 1901/2006.
    Background therapy
    		 STZ based chemotherapy, STZ-5FU, is the actual standard of care for advanced pancreatic Neuroendocrine tumours (pNETS) in the European Union. Everolimus has been recently approved for its use in advanced pNETs by the Food and Drug Administration (FDA) and in Europe by the European Medical Agency (EMA). A randomized study is needed to have a clear knowledge about the best sequence for its administration; this is, before or after palliative chemotherapy. There may or may not be any benefits from giving first each other treatment of the study. The information obtained from this study will help the physician improve the treatment and management of patients with advanced pNET. This study was planned to compare STZ-5FU chemotherapy followed by everolimus upon progression versus the reverse sequence. However sequential studies with pNETs are hard to be managed in terms of time and costs. Therefore the protocol was amended to have PFS1 (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression free survival after both STZ based chemotherapy and Everolimus or the reverse order) as secondary endpoint. This information will be extremely valuable for the day to day clinical practice of NET oncologists
    Evidence for comparator
    		 The first randomized phase III trial in pancreatic neuroendocrine tumours (pNETs) was performed by Moertel in 1980. 84 patients with pNETs were randomized to receive the combination of streptozocin (STZ) and 5-fluorouracil (5FU) or STZ as a single agent. The combination arm demonstrated superior results to those of the monotherapy arm in terms of overall response rate (ORR) (63% vs 36% respectively) and median overall survival (mOS) (26 versus 16.5 months), although the difference in mOS was not statistically significant. STZ based chemotherapy, STZ-5FU, is the actual standard of care for advanced pNETS in the European Union (ENETS guidelines; Neuroendocrinology 2012)14. Everolimus has been recently approved for its use in advanced pNETs by the FDA and in Europe by the EMA . A randomized study is needed to have a clear knowledge about the best sequence for its administration; this is, before or after palliative chemotherapy. There may or may not be any benefits from giving first each other treatment of the study. The information obtained from this study will help the physician improve the treatment and management of patients with pNET. Variation of treatment choices will still depend on physician expertise, the complexity of the treatment center and, access to novel treatments (ENETS guidelines, Neuroendocrinology 2016)26. There are not randomized trials comparing Progression Free Survival (PFS) of STZ based chemotherapy versus Everolimus. This study was planned to compare STZ-5FU chemotherapy followed by everolimus 10 mg/day upon progression versus the reverse sequence. However sequential studies with pNETs are hard to be managed in terms of time and costs. Therefore we propose to have PFS1 (progression free survival after course 1) as primary endpoint and PFS2 (i.e. progression free survival after both STZ based chemotherapy and Everolimus or the reverse order) as secondary endpoint. This information will be extremely valuable for the day to day clinica
    Actual start date of recruitment
    01 Jul 2014
    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
    Netherlands: 10
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Italy: 19
    Worldwide total number of subjects
    141
    EEA total number of subjects
    136
    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)
    71
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomised phase III open label and cross-over treatment study to compare the efficacy and safety of everolimus followed by chemotherapy upon progression or the reverse sequence, in advanced progressive pNETs. The SEQTOR study design was based on clinical practice.

    Pre-assignment
    Screening details
    		 Screening period : 28 days. The screening assessments included: informed consent, demographics, inclusion/exclusion criteria, relevant clinical history, confirmation advanced NET, diagnosis and extension of cancer (disease metastasis sites), previous anticancer treatment, radiation therapy and surgery, physical examination, QoL question, CT scan

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sequence A, Drug: Everolimus First
    Arm description
    		 Sequence A, drug: everolimus first Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus followed by STZ-5FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    powder for prolonged-release oral suspension, Solution for infusion
    Routes of administration
    Oral use, Solution for infusion
    Dosage and administration details
    Drug: Drug: Everolimus 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops. Other Names: Afinitor Drug: STZ-5FU 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-5 every 6 weeks (Moertel) or 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-3, and then 1 day with 1g/m2 and 1 day 400mg/m2 5-FU every 3 weeks (Uppsala). Number of Cycles: until progression or unacceptable toxicity develops.

    Arm title
    		 Experimental: Sequence B, drug: STZ - 5FU first
    Arm description
    		 STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)
    Arm type
    		 Experimental

    Investigational medicinal product name
    STZ - 5FU followed by Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Drug: STZ-5FU 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-5 every 6 weeks (Moertel) or 0,5g/m2 STZ on days 1-5 and 400mg/m2 5-FU on days 1-3, and then 1 day with 1g/m2 and 1 day 400mg/m2 5-FU every 3 weeks (Uppsala). Number of Cycles: until progression or unacceptable toxicity develops. Drug: Drug: Everolimus 10mg/daily, oral. Number of Cycles: until progression or unacceptable toxicity develops.

    Number of subjects in period 1
    		Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Started
    72
    69
    Completed
    72
    69

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sequence A, Drug: Everolimus First
    Reporting group description
    		 Sequence A, drug: everolimus first Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).

    Reporting group title
    Experimental: Sequence B, drug: STZ - 5FU first
    Reporting group description
    		 STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)

    Reporting group values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first Total
    Number of subjects
    		 72 69 141
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at randomization
    Units: years
        median (full range (min-max))
    		 58 (33 to 83) 58 (33 to 80) -
    Gender categorical
    Sex: Female, Male Measure Type: Count of Participants
    Units: Subjects
        Female
    		 31 25 56
        Male
    		 41 44 85
    ECOG-PS
    he ECOG Performance Status Scale is a widely used method to assess the functional status of a patient. The scale ranges from a score of 0 (Fully active, able to carry on all pre-disease performance without restriction) to 5 (death). Reported at randomization (Baseline)
    Units: Subjects
        score 0
    		 50 47 97
        score 1
    		 20 22 42
        score 2
    		 2 0 2
    M-distant metastasesat inclusion
    Presence of distant metastasis at the moment of randomization (baseline). Mx indicates that metastasis were assessed but the status of the patient regarding presence of metastasis could not be determined. M0 indicates no presence of distal metastasis. M1 indicates presence of distant metastasis and afectation of distant organs
    Units: Subjects
        Mx
    		 1 1 2
        M0
    		 2 6 8
        M1
    		 69 62 131
    Bone metastases at randomization
    Number of patients who have distant organs affected by metastasis at randomization (Baseline). A patient may have more than one organ affected.
    Units: Subjects
        Yes
    		 7 10 17
        No
    		 65 59 124
    Lung metastasis at randomization
    Number of patients who have distant organs affected by metastasis at randomization (Baseline). A patient may have more than one organ affected.
    Units: Subjects
        Yes
    		 2 3 5
        No
    		 70 66 136
    Liver metastasis at randomization
    Number of patients who have distant organs affected by metastasis at randomization (Baseline). A patient may have more than one organ affected.
    Units: Subjects
        Yes
    		 61 56 117
        No
    		 11 13 24
    Lymph nodes metastasis at randomization
    Number of patients who have distant organs affected by metastasis at randomization (Baseline). A patient may have more than one organ affected.
    Units: Subjects
        Yes
    		 4 6 10
        No
    		 68 63 131
    Ki-67 index
    Ki-67 is a protein found only in cells that are dividing. A high Ki-67 proliferation index means that many cells are dividing rapidly and that the cancer is likely to grow and spread. Here we used the categories used by the WHO classification for neuroendocrine tumors
    Units: Subjects
        ≤ 2
    		 9 14 23
        3-20
    		 62 51 113
        Unknown
    		 1 4 5
    Tumor Grade
    Tumor grade at randomization (baseline) using the World health organization (WHO) grading system for neuroendocrine tumors: G1: < 2 mitoses per 2 mm2 and/or Ki-67 index ≤2%, G2: 2-20 mitoses per 2 mm2 and/or Ki-67index >2% and ≤ 20%
    Units: Subjects
        Grade 1
    		 9 12 21
        Grade 2
    		 63 55 118
        Unknown
    		 0 2 2
    Number of previous systemic treatment lines
    Units: Subjects
        0 prior treatment lines
    		 36 43 79
        1 prior treatment line
    		 32 22 54
        2 prior treatment lines
    		 4 4 8
    Previous treatment with somatostatin analogues
    Units: Subjects
        Yes
    		 31 24 55
        No
    		 41 45 86
    Previous treatment with radiopharmaceuticals
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 68 66 134
    Previous treatments - others
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 71 68 139

    End points

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    End points reporting groups
    Reporting group title
    Sequence A, Drug: Everolimus First
    Reporting group description
    		 Sequence A, drug: everolimus first Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).

    Reporting group title
    Experimental: Sequence B, drug: STZ - 5FU first
    Reporting group description
    		 STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)

    Primary: First Progression Free Survival (PFS1)

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    End point title
    		 First Progression Free Survival (PFS1)
    End point description
    Proportion of patients who are alive without progression to Course 1 from the date of randomization in STZ based CT vs Everolimus arms Definitions for PFS rate for course 1 at 12 months: No: number (proportion) of patients who were not alive andprogression free according to the respective definition (main,conservative, and optimistic); Yes: number (proportion) of patients who were alive andprogression free according to the respective definition (main,conservative, and optimistic).
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    72
    69
    Units: Percentage of patients
        number (confidence interval 95%)
    71.4 (59.4 to 81.6)
    61.8 (49.2 to 73.3)
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.229
    Method
    		 Regression, Cox
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.32

    Secondary: Second Progression Free Survival (Second PFS)

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    End point title
    		 Second Progression Free Survival (Second PFS)
    End point description
    PFS of Course 1 (PFS1) + interval between treatments + PFS of Course 2 (PFS2), where PFS1 represents progression free survival of Course 1 and PFS2 represents progression free survival of Course 2
    End point type
    Secondary
    End point timeframe
    Until the end of study every 12 weeks, approximately up to 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    72
    69
    Units: months
        median (confidence interval 95%)
    37.5 (27.1 to 53.7)
    32.6 (23.7 to 41.1)
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.135 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.19
    Notes
    [1] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Progression-free Survival (PFS) to First Treatment

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    End point title
    		 Progression-free Survival (PFS) to First Treatment
    End point description
    Time from the date of randomization to the date of first disease progression.
    End point type
    Secondary
    End point timeframe
    Throughout the study period every 12 weeks, approximately up to 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    72
    69
    Units: Months
        median (confidence interval 95%)
    19.4 (16.8 to 27.3)
    22.7 (13.3 to 28.6)
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.474 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.75
    Notes
    [2] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Adverse Events (AEs) Rate

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    End point title
    		 Adverse Events (AEs) Rate
    End point description
    Number of patients experiending serious adverse events (SAEs)
    End point type
    Secondary
    End point timeframe
    Throughout the study period in continous monitoring at every visit for approximately up to 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    69 [3]
    66 [4]
    Units: Patients
        Experienced SAEs
    28
    26
        Not experienced SAEs
    41
    40
    Notes
    [3] - Only patients who received study drug
    [4] - Only patients who received study drug
    No statistical analyses for this end point

    Secondary: Frequency of Dose Modifications to First Treatment

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    End point title
    		 Frequency of Dose Modifications to First Treatment
    End point description
    Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period
    End point type
    Secondary
    End point timeframe
    Throughout the study period, approximately up to 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    68 [5]
    66 [6]
    Units: Patients
        Interrupted or reduced doses
    41
    9
        Not Interrupted or reduced doses
    27
    57
    Notes
    [5] - Only patients who received study drug
    [6] - Only patients who received study drug
    Statistical analysis title
    		 Fisher test
    Comparison groups
    Experimental: Sequence B, drug: STZ - 5FU first v Sequence A, Drug: Everolimus First
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [7] - significant differences between both arms is assumed in case p-val <0.0

    Secondary: Best Overall Response (BOR) to First Study Treatment

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    End point title
    		 Best Overall Response (BOR) to First Study Treatment
    End point description
    Best response achieved with the first study treatment according to RECIST V1.0
    End point type
    Secondary
    End point timeframe
    Throughout the study period, every 12 weeks up to approximately 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    69 [8]
    66 [9]
    Units: Patients
        Complete response (CR)
    3
    3
        Partial response (PR)
    5
    17
        Stable disease (SD)
    58
    35
        Progression of the disease (PD)
    2
    9
        Not evaluable (NE)
    1
    2
    Notes
    [8] - Only patients having tumor assessments
    [9] - Only patients having tumor assessments
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) to First Study Treatment

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    End point title
    		 Objective Response Rate (ORR) to First Study Treatment
    End point description
    The ORR is defined as the number of patients having as their BOR tofirst treatment either Complete response (CR) or Partial Response(PR) measured by RECIST criteria version 1.0.
    End point type
    Secondary
    End point timeframe
    Throughout the study period every 12 weeks, up to approximately 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    69 [10]
    66 [11]
    Units: Patients
        CR / PR
    8
    20
        SD / PD / NE
    61
    46
    Notes
    [10] - Only patients having tumor assessments
    [11] - Only patients having tumor assessments
    Statistical analysis title
    		 Fisher test
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [12]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [12] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Frequency of Dose Modifications to Second Treatment

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    End point title
    		 Frequency of Dose Modifications to Second Treatment
    End point description
    Percentage of patients who require a dose reduction or interruption for management of adverse events during the study period
    End point type
    Secondary
    End point timeframe
    Throughout the study period, approximately up to 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    36 [13]
    33 [14]
    Units: Patients
        Interrupt or reduced doses
    5
    18
        Not interrupt or reduced doses
    31
    15
    Notes
    [13] - Patients starting second line treatment
    [14] - Patients starting second line treatment
    Statistical analysis title
    		 Fisher test
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [15]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [15] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The median OS defined as the time from the date of randomization until death from any cause. This is estimated by kaplan meier method.
    End point type
    Secondary
    End point timeframe
    Throughout the study period, up to approximately 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    72
    69
    Units: months
        median (confidence interval 95%)
    61.7 (49.1 to 100)
    50.6 (40.9 to 64.5)
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.168 [16]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.37
    Notes
    [16] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Best Overall Response (BOR) to Second Study Treatment

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    End point title
    		 Best Overall Response (BOR) to Second Study Treatment
    End point description
    Best response achieved with the second study treatment according to RECIST V1.0
    End point type
    Secondary
    End point timeframe
    Throughout the study period, every 12 weeks up to approximately 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    36 [17]
    33 [18]
    Units: Patients
        Complete response (CR)
    1
    0
        Partial response (PR)
    10
    3
        Stable disease (SD)
    15
    20
        Progression of the disease (PD)
    8
    8
        Not evaluable (NE)
    2
    2
    Notes
    [17] - Patients starting second line treatment
    [18] - Patients starting second line treatment
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) to Second Study Treatment

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    End point title
    		 Objective Response Rate (ORR) to Second Study Treatment
    End point description
    The ORR is defined as the number of patients having as their BOR to second treatment either Complete response (CR) or Partial Response (PR) measured by RECIST criteria version 1.0.
    End point type
    Secondary
    End point timeframe
    Throughout the study period every 12 weeks, up to approximately 5 years
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    36 [19]
    33 [20]
    Units: Patients
        CR / PR
    11
    3
        SD / PD / NE
    25
    30
    Notes
    [19] - Patients starting the second line treatment
    [20] - Patients starting the second line treatment
    Statistical analysis title
    		 Fisher test
    Comparison groups
    Sequence A, Drug: Everolimus First v Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.072 [21]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [21] - significant differences between both arms is assumed in case p-val <0.05

    Secondary: Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 GlobalHealth Status

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    End point title
    		 Quality of Life Questionnaire (QLQ). The EORTC QLQ-C30 GlobalHealth Status
    End point description
    Patient self-reported quality of life (QoL) was assessed using the European Organisation for Research and Treatment of Cance r(EORTC) QLQ-C30 questionnaire and the specific module for NETs, QLQ-GINET21. These questionnaires have a puntuation that ranges from 100 (best patient performance) to 0 (worse patient performance). Here we report the total QLQ-C30 score.
    End point type
    Secondary
    End point timeframe
    Before any dose of study treatment (basal), before the first dose of the second treatment at line 2 cycle 1 (L2C1) and after completion of both treatments (EOT)
    End point values
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Number of subjects analysed
    47 [22]
    49 [23]
    Units: Score
    arithmetic mean (standard deviation)
        Basal
    78.3 ( 17.6 )
    77.8 ( 12.1 )
        L2C1
    75.1 ( 16 )
    84.1 ( 9.5 )
        EOT
    68.4 ( 15.2 )
    75.4 ( 17.9 )
    Notes
    [22] - Patients completing the QLQ questionnaires at any timepoint
    [23] - Patients completing the QLQ questionnaires at any timepoint
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period, approximately up to 5 years of follow-up
    Adverse event reporting additional description
    Reported during the first treatment assigned in each arm. Reported in the safety population, comprising only patients who received at least one dose of the study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Sequence A, Drug: Everolimus First
    Reporting group description
    		 Sequence A, drug: everolimus first Everolimus (10mg/daily, oral) followed by STZ-5FU (injection/infusion; Moertel or Uppsala regime).

    Reporting group title
    Experimental: Sequence B, drug: STZ - 5FU first
    Reporting group description
    		 STZ-5FU (injection/infusion; Moertel or Uppsala regime) followed by Everolimus (10 mg/ daily, oral)

    Serious adverse events
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 69 (40.58%)
    26 / 66 (39.39%)
         number of deaths (all causes)
    26
    35
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Liver metastasis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urotelial carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    4 / 69 (5.80%)
    4 / 66 (6.06%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased urea
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (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
    Presyncope
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 69 (4.35%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomach pain
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute cholangitis
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localized edema
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash acneiform
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Calculi
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteremia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection without focus
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 69 (4.35%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycemia
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridemia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sequence A, Drug: Everolimus First Experimental: Sequence B, drug: STZ - 5FU first
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 69 (98.55%)
    62 / 66 (93.94%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 69 (11.59%)
    1 / 66 (1.52%)
         occurrences all number
    9
    1
    Thromboembolic event
         subjects affected / exposed
    2 / 69 (2.90%)
    4 / 66 (6.06%)
         occurrences all number
    2
    6
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    17 / 69 (24.64%)
    5 / 66 (7.58%)
         occurrences all number
    33
    8
    Fatigue
         subjects affected / exposed
    39 / 69 (56.52%)
    37 / 66 (56.06%)
         occurrences all number
    76
    159
    Fever
         subjects affected / exposed
    14 / 69 (20.29%)
    5 / 66 (7.58%)
         occurrences all number
    21
    8
    Flu like symptoms
         subjects affected / exposed
    10 / 69 (14.49%)
    9 / 66 (13.64%)
         occurrences all number
    17
    10
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 69 (5.80%)
    4 / 66 (6.06%)
         occurrences all number
    4
    4
    Pain in extremity
         subjects affected / exposed
    3 / 69 (4.35%)
    6 / 66 (9.09%)
         occurrences all number
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 69 (11.59%)
    5 / 66 (7.58%)
         occurrences all number
    9
    6
    Dyspnea
         subjects affected / exposed
    6 / 69 (8.70%)
    6 / 66 (9.09%)
         occurrences all number
    7
    7
    Epistaxis
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 66 (0.00%)
         occurrences all number
    7
    0
    Pneumonitis
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 66 (0.00%)
         occurrences all number
    10
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 69 (5.80%)
    8 / 66 (12.12%)
         occurrences all number
    4
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 69 (11.59%)
    2 / 66 (3.03%)
         occurrences all number
    11
    2
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 69 (4.35%)
    4 / 66 (6.06%)
         occurrences all number
    4
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 69 (10.14%)
    1 / 66 (1.52%)
         occurrences all number
    10
    1
    Cholesterol high
         subjects affected / exposed
    10 / 69 (14.49%)
    2 / 66 (3.03%)
         occurrences all number
    16
    2
    Creatinine increased
         subjects affected / exposed
    4 / 69 (5.80%)
    6 / 66 (9.09%)
         occurrences all number
    5
    16
    GGT increased
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 66 (0.00%)
         occurrences all number
    5
    0
    Weight loss
         subjects affected / exposed
    9 / 69 (13.04%)
    5 / 66 (7.58%)
         occurrences all number
    12
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 69 (1.45%)
    4 / 66 (6.06%)
         occurrences all number
    1
    6
    Dysgeusia
         subjects affected / exposed
    8 / 69 (11.59%)
    5 / 66 (7.58%)
         occurrences all number
    10
    9
    Headache
         subjects affected / exposed
    7 / 69 (10.14%)
    3 / 66 (4.55%)
         occurrences all number
    11
    5
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    10 / 69 (14.49%)
    3 / 66 (4.55%)
         occurrences all number
    22
    6
    Febrile neutropenia
         subjects affected / exposed
    2 / 69 (2.90%)
    5 / 66 (7.58%)
         occurrences all number
    2
    7
    Platelet count decreased
         subjects affected / exposed
    10 / 69 (14.49%)
    7 / 66 (10.61%)
         occurrences all number
    23
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 69 (20.29%)
    17 / 66 (25.76%)
         occurrences all number
    21
    27
    Constipation
         subjects affected / exposed
    10 / 69 (14.49%)
    15 / 66 (22.73%)
         occurrences all number
    11
    24
    Diarrhea
         subjects affected / exposed
    26 / 69 (37.68%)
    19 / 66 (28.79%)
         occurrences all number
    63
    46
    Dry mouth
         subjects affected / exposed
    3 / 69 (4.35%)
    4 / 66 (6.06%)
         occurrences all number
    5
    5
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 69 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    0
    5
    Mouth ulcer
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 66 (3.03%)
         occurrences all number
    9
    2
    Mucositis oral
         subjects affected / exposed
    34 / 69 (49.28%)
    16 / 66 (24.24%)
         occurrences all number
    87
    26
    Nausea
         subjects affected / exposed
    21 / 69 (30.43%)
    26 / 66 (39.39%)
         occurrences all number
    33
    50
    Stomach pain
         subjects affected / exposed
    6 / 69 (8.70%)
    3 / 66 (4.55%)
         occurrences all number
    7
    3
    Vomiting
         subjects affected / exposed
    12 / 69 (17.39%)
    13 / 66 (19.70%)
         occurrences all number
    15
    23
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    12 / 69 (17.39%)
    3 / 66 (4.55%)
         occurrences all number
    14
    5
    Nail changes
         subjects affected / exposed
    4 / 69 (5.80%)
    2 / 66 (3.03%)
         occurrences all number
    7
    2
    Nail ridging
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    5 / 69 (7.25%)
    4 / 66 (6.06%)
         occurrences all number
    7
    5
    Pruritus
         subjects affected / exposed
    7 / 69 (10.14%)
    8 / 66 (12.12%)
         occurrences all number
    8
    10
    Rash acneiform
         subjects affected / exposed
    26 / 69 (37.68%)
    4 / 66 (6.06%)
         occurrences all number
    39
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 69 (1.45%)
    4 / 66 (6.06%)
         occurrences all number
    1
    6
    Proteinuria
         subjects affected / exposed
    6 / 69 (8.70%)
    5 / 66 (7.58%)
         occurrences all number
    8
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 69 (7.25%)
    7 / 66 (10.61%)
         occurrences all number
    8
    8
    Cramps
         subjects affected / exposed
    3 / 69 (4.35%)
    4 / 66 (6.06%)
         occurrences all number
    3
    6
    Infections and infestations
    Lung infection
         subjects affected / exposed
    7 / 69 (10.14%)
    0 / 66 (0.00%)
         occurrences all number
    8
    0
    Pharyngitis
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Skin infection
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 66 (0.00%)
         occurrences all number
    4
    0
    Urinary tract infection
         subjects affected / exposed
    11 / 69 (15.94%)
    3 / 66 (4.55%)
         occurrences all number
    19
    3
    Upper respiratory infection
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 66 (0.00%)
         occurrences all number
    5
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    16 / 69 (23.19%)
    12 / 66 (18.18%)
         occurrences all number
    23
    24
    Hyperglycemia
         subjects affected / exposed
    23 / 69 (33.33%)
    9 / 66 (13.64%)
         occurrences all number
    36
    14
    Hypertriglyceridemia
         subjects affected / exposed
    8 / 69 (11.59%)
    0 / 66 (0.00%)
         occurrences all number
    18
    0
    Hypokalemia
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         occurrences all number
    7
    1
    Hypomagnesemia
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         occurrences all number
    10
    1
    Hypophosphatemia
         subjects affected / exposed
    6 / 69 (8.70%)
    1 / 66 (1.52%)
         occurrences all number
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2014
    Change on main variable and sample size.
    26 Nov 2014
    New Instututions are included. Enlargement of study timing

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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