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    Clinical Trial Results:
    Phase 2 Trial of MLN0264 in Previously Treated Patients with Advanced or Metastatic Pancreatic Adenocarcinoma Expressing Guanylyl Cyclase C (GCC)

    Summary
    EudraCT number
    2014-000805-11
    Trial protocol
    IT   ES   BE   GB  
    Global end of trial date
    15 Jan 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    29 Jun 2017
    First version publication date
    31 Jan 2017
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Updates due to QA comments from ClinicalTrials.gov.

    Trial information

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    Trial identification
    Sponsor protocol code
    C26003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02202785
    WHO universal trial number (UTN)
    U1111-1155-8964
    Sponsors
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc.
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Takeda, +1 877-825-3327,
    Scientific contact
    Medical Director, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy, safety and tolerability of MLN0264 in patients with advanced or metastatic guanylyl cyclase C (GCC)-positive adenocarcinoma of the pancreas.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Sep 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
    Belgium: 5
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    43
    EEA total number of subjects
    23
    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)
    21
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 26 investigative sites in Belgium, Spain, United Kingdom and the United States from 24 September 2014 to 15 January 2016.

    Pre-assignment
    Screening details
    Participants with a diagnosis of Pancreatic adenocarcinoma were enrolled in 1 treatment group, MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    MLN0264 1.8 mg/kg (GCC Low)
    Arm description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 4 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN0264
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle

    Arm title
    MLN0264 1.8 mg/kg (GCC Intermediate)
    Arm description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN0264
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle

    Arm title
    MLN0264 1.8 mg/kg (GCC High)
    Arm description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 6 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score >120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
    Arm type
    Experimental

    Investigational medicinal product name
    MLN0264
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle

    Number of subjects in period 1
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Started
    11
    15
    17
    Completed
    0
    0
    0
    Not completed
    11
    15
    17
         Study Terminated by Sponsor
             1
             6
             4
         Consent withdrawn by subject
             -
             1
             -
         Reason not Specified
             10
             7
             13
         Lost to follow-up
             -
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MLN0264 1.8 mg/kg (GCC Low)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 4 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Reporting group title
    MLN0264 1.8 mg/kg (GCC Intermediate)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Reporting group title
    MLN0264 1.8 mg/kg (GCC High)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 6 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score >120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Reporting group values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High) Total
    Number of subjects
    11 15 17 43
    Age categorical
    Units: Subjects
        44 to 81 years
    11 15 17 43
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 11.2 65.5 ± 7.41 62.9 ± 10.88 -
    Gender, Male/Female
    Units: Participants
        Female
    8 11 4 23
        Male
    3 4 13 20
    Race/Ethnicity, Customized
    Units: Subjects
        White
    9 15 17 41
        Black or African American
    1 0 0 1
        Not Reported
    1 0 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    3 1 0 4
        Not Hispanic or Latino
    8 14 17 39
    Study Specific Characteristic | Height
    Units: cm
        arithmetic mean (standard deviation)
    163 ± 13.2 162.1 ± 9.54 170.6 ± 8.51 -
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (standard deviation)
    60.98 ± 18.769 63.45 ± 18.465 71.2 ± 17.456 -
    Study Specific Characteristic | Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    1.65 ± 0.3045 1.679 ± 0.2761 1.827 ± 0.2575 -
    Subject analysis sets

    Subject analysis set title
    MLN0264 1.8 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

    Subject analysis set title
    MLN0264 1.8 mg/kg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

    Subject analysis sets values
    MLN0264 1.8 mg/kg MLN0264 1.8 mg/kg
    Number of subjects
    43
    1
    Age categorical
    Units: Subjects
        44 to 81 years
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender, Male/Female
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
    41
    1
        Black or African American
    1
    0
        Not Reported
    1
    0
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    4
    0
        Not Hispanic or Latino
    39
    1
    Study Specific Characteristic | Height
    Units: cm
        arithmetic mean (standard deviation)
    ±
    ±
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (standard deviation)
    ±
    ±
    Study Specific Characteristic | Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    MLN0264 1.8 mg/kg (GCC Low)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 4 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Reporting group title
    MLN0264 1.8 mg/kg (GCC Intermediate)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Reporting group title
    MLN0264 1.8 mg/kg (GCC High)
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 6 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score >120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

    Subject analysis set title
    MLN0264 1.8 mg/kg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

    Subject analysis set title
    MLN0264 1.8 mg/kg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

    Primary: Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

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    End point title
    Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) [1]
    End point description
    ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
    End point type
    Primary
    End point timeframe
    Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (Up to 16 months)
    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: Only descriptive statistics was planned for this endpoint.
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    13
    15
    Units: percentage of participants
    0
    8
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings

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    End point title
    Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
    End point description
    Participants with at least one post-baseline potentially clinically significant serum chemistry, hematology, coagulation or urinalysis result. Clinically significant results are those that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
    End point type
    Secondary
    End point timeframe
    Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 7.9 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    43
    Units: Participants
        Chemistry
    20
        Hematology
    16
        Coagulation
    23
        Urinalysis
    0
    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
    PFS is defined as the time in days from the date of first study drug administration to the date of first documentation of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    End point type
    Secondary
    End point timeframe
    Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 13.9 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    13
    15
    Units: days
        median (full range (min-max))
    39 (9 to 82)
    42 (21 to 218)
    41 (16 to 137)
    No statistical analyses for this end point

    Secondary: Number of Participants With Potentially Clinically Significant Vital Signs Findings

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    End point title
    Number of Participants With Potentially Clinically Significant Vital Signs Findings
    End point description
    Participants with at least one potentially clinically significant post-baseline vital sign finding including measurements of diastolic and systolic blood pressure, heart rate, and oral temperature.
    End point type
    Secondary
    End point timeframe
    Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 7.9 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    43
    Units: Participants
    0
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response is defined as the time from the date of first documentation of a Partial Response or better to the date of first documentation of disease progression or relapse based on investigator assessment using RECIST version 1.1 guidelines. Per RECIST version 1.1 for target lesions and assessed by MRI: CR, Disappearance of all target lesions; PR, >=30% decrease in the sum of the longest diameter of target lesions.
    End point type
    Secondary
    End point timeframe
    From first documented response until disease progression (Up to 16 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    1
    Units: days
        median (full range (min-max))
    103 (103 to 103)
    No statistical analyses for this end point

    Secondary: Disease Control Rate

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    End point title
    Disease Control Rate
    End point description
    Disease control rate is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) with a minimum of 12 weeks' duration. Investigator response is based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter (LD) since the treatment started.
    End point type
    Secondary
    End point timeframe
    Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 13.9 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    13
    15
    Units: percentage of participants
    0
    23
    20
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is defined as the time in days from the date of first study drug administration to the date of death.
    End point type
    Secondary
    End point timeframe
    Until death or 6 months after the last patient completes treatment—whichever occurs first (Up to 16 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    15
    17
    Units: days
        median (full range (min-max))
    162 (36 to 282)
    140 (43 to 443)
    162 (49 to 435)
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Serum Concentration for MLN0264

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    End point title
    Cmax: Maximum Observed Serum Concentration for MLN0264
    End point description
    Cmax was not a pre-specified secondary outcome measure. No data was collected.
    End point type
    Secondary
    End point timeframe
    Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    0 [2]
    Units: μg/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [2] - No data was collected for this analysis due to early termination.
    No statistical analyses for this end point

    Secondary: Serum Concentration of Monomethyl Auristatin E (MMAE)

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    End point title
    Serum Concentration of Monomethyl Auristatin E (MMAE)
    End point description
    Blood samples were collected and sent to a laboratory to be tested for MMAE.
    End point type
    Secondary
    End point timeframe
    Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    43
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose
    0.296 ± 0.1624
        Cycle 1 Day 1, 4 Hours Post-Dose
    2.438 ± 1.3015
        Cycle 1 Day 3, 48 Hours Post-Dose (n=41)
    5.202 ± 2.811
        Cycle 1 Day 4, 72 Hours Post-Dose (n=39)
    4.918 ± 2.3653
        Cycle 1 Day 8, 168 Hours Post-Dose (n=43)
    2.994 ± 2.1173
        Cycle 1 Day 15, 336 Hours Post-Dose (n=37)
    0.58 ± 0.5073
        Cycle 2 Day 1, Pre-Dose (n=37)
    0.128 ± 0.1304
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=37)
    0.405 ± 0.3351
        Cycle 2 Day 1, 4 Hours Post-Dose (n=37)
    2.665 ± 1.6053
        Cycle 2 Day 3, 48 Hours Post-Dose (n=34)
    6.223 ± 3.5926
        Cycle 2 Day 4, 72 Hours Post-Dose (n=32)
    5.808 ± 3.6296
        Cycle 2 Day 8, 168 Hours Post-Dose (n=34)
    2.789 ± 2.0437
        Cycle 2 Day 15, 336 Hours Post-Dose (n=28)
    0.56 ± 0.5332
        Cycle 3 Day 1, Pre-Dose (n=9)
    0.145 ± 0.1318
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=9)
    0.395 ± 0.3514
        Cycle 3 Day 1, 4 Hours Post-Dose (n=9)
    2.237 ± 1.6402
        Cycle 3 Day 3, 48 Hours Post-Dose (n=8)
    6.563 ± 5.2034
        Cycle 3 Day 4, 72 Hours Post-Dose (n=8)
    6.563 ± 6.2902
        Cycle 3 Day 8, 168 Hours Post-Dose (n=7)
    2.826 ± 2.0234
        Cycle 3 Day 15, 336 Hours Post-Dose (n=7)
    1.155 ± 1.2808
        Cycle 4 Day 1, Pre-Dose (n=7)
    0.232 ± 0.2877
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=7)
    0.446 ± 0.4029
        Cycle 5 Day 1, Pre-Dose (n=5)
    0.09 ± 0.0594
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=5)
    0.249 ± 0.1004
        Cycle 6 Day 1, Pre-Dose (n=5)
    0.105 ± 0.0469
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=5)
    0.269 ± 0.1037
        Cycle 6 Day 4, 72 Hours Post-Dose (n=5)
    4.234 ± 1.3134
        Cycle 6 Day 8, 168 Hours Post-Dose (n=5)
    2.002 ± 0.9691
        Cycle 7 Day 1, Pre-Dose (n=2)
    0.125 ± 0.0365
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=2)
    0.277 ± 0.0806
        Cycle 8 Day 1, Pre-Dose (n=2)
    0.108 ± 0.0288
        Cycle 8 Day 1, 10 Minute Post-Dose (n=2)
    0.257 ± 0.0481
        Cycle 9 Day 1, Pre-Dose (n=2)
    0.05 ± 0.019
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    0.19 ± 0.0361
        Cycle 10 Day 1, Pre-Dose (n=1)
    0.132 ± 0
        Cycle 10 Day 1, 10 Minutes Post-Dose (n=1)
    0.385 ± 0
        End of Treatment (n=27)
    0.137 ± 0.1695
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 7.9 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    15
    17
    Units: Participants
        AEs
    11
    15
    17
        SAEs
    3
    7
    9
    No statistical analyses for this end point

    Secondary: Guanylyl Cyclase C (GCC) H-score assessed by immunohistochemistry (IHC)

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    End point title
    Guanylyl Cyclase C (GCC) H-score assessed by immunohistochemistry (IHC)
    End point description
    GCC H-score is based on the sum of the 0 to 300 H-score for cytoplasmic staining and the 0 to 300 H-score for apical staining for a total possible H-score 0 to 600. Separate consent is required to obtain archival tumor specimens for GCC expression assessment prior to screening.

    End point type
    Secondary
    End point timeframe
    From pre-screening through end of study (approximately 18 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    15
    17
    Units: Scores on a scale
    arithmetic mean (full range (min-max))
        Guanylyl Cyclase C (GCC) H-score Assessed by Immun
    29.6 (10 to 55)
    84 (60 to 110)
    204.2 (120 to 355)
    No statistical analyses for this end point

    Secondary: MLN0264 Serum Concentrations

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    End point title
    MLN0264 Serum Concentrations
    End point description
    Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.
    End point type
    Secondary
    End point timeframe
    Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    43
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose
    36.647 ± 10.0936
        Cycle 1 Day 1, 4 Hours Post-Dose
    27.898 ± 8.4886
        Cycle 1 Day 3, 48 Hours Post-Dose (n=41)
    6.95 ± 1.9173
        Cycle 1 Day 4, 72 Hours Post-Dose (n=39)
    4.758 ± 1.5349
        Cycle 1 Day 8, 168 Hours Post-Dose (n=43)
    1.563 ± 0.5818
        Cycle 1 Day 15, 336 Hours Post-Dose (n=37)
    0.582 ± 0.2331
        Cycle 2 Day 1, Pre-Dose (n=37)
    0.261 ± 0.1643
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=37)
    30.856 ± 9.9483
        Cycle 2 Day 1, 4 Hours Post-Dose (n=37)
    26.691 ± 7.9664
        Cycle 2 Day 3, 48 Hours Post-Dose (n=35)
    7.021 ± 2.4977
        Cycle 2 Day 4, 72 Hours Post-Dose (n=32)
    4.432 ± 1.6115
        Cycle 2 Day 8, 168 Hours Post-Dose (n=34)
    1.681 ± 0.78
        Cycle 2 Day 15, 336 Hours Post-Dose (n=27)
    0.692 ± 0.3038
        Cycle 3 Day 1, Pre-Dose (n=9)
    0.431 ± 0.1481
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=9)
    34.978 ± 5.335
        Cycle 3 Day 1, 4 Hours Post-Dose (n=9)
    26.393 ± 3.3557
        Cycle 3 Day 3, 48 Hours Post-Dose (n=8)
    9.486 ± 2.9593
        Cycle 3 Day 4, 72 Hours Post-Dose (n=8)
    6.579 ± 1.8102
        Cycle 3 Day 8, 168 Hours Post-Dose (n=7)
    1.701 ± 0.4201
        Cycle 3 Day 15, 336 Hours Post-Dose (n=7)
    0.89 ± 0.2276
        Cycle 4 Day 1, Pre-Dose (n=7)
    0.49 ± 0.1881
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=7)
    37.166 ± 9.3823
        Cycle 5 Day 1, Pre-Dose (n=5)
    0.446 ± 0.2197
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=5)
    31.06 ± 8.3802
        Cycle 6 Day 1, Pre-Dose (n=5)
    0.412 ± 0.2183
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=5)
    23.204 ± 12.9564
        Cycle 6 Day 4, 72 Hours Post-Dose (n=5)
    4.689 ± 0.9286
        Cycle 6 Day 8, 168 Hours Post-Dose (n=5)
    1.41 ± 0.2504
        Cycle 7 Day 1, Pre-Dose (n=2)
    0.277 ± 0.0863
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=2)
    34.56 ± 6.5337
        Cycle 8 Day 1, Pre-Dose (n=2)
    2.047 ± 2.6517
        Cycle 8 Day 1, 10 Minute Post-Dose (n=2)
    27.12 ± 4.8649
        Cycle 9 Day 1, Pre-Dose (n=2)
    0.178 ± 0.0467
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    31.88 ± 0.4808
        Cycle 10 Day 1, Pre-Dose (n=1)
    0.207 ± 0
        Cycle 10 Day 1, 10 Minutes Post-Dose (n=1)
    20.86 ± 0
        End of Treatment (n=27)
    0.324 ± 0.2618
    No statistical analyses for this end point

    Secondary: Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

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    End point title
    Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
    End point description
    Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.
    End point type
    Secondary
    End point timeframe
    Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    43
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose
    37.599 ± 9.4299
        Cycle 1 Day 1, 4 Hours Post-Dose
    32.974 ± 8.1824
        Cycle 1 Day 3, 48 Hours Post-Dose (n=41)
    14.051 ± 4.0368
        Cycle 1 Day 4, 72 Hours Post-Dose (n=39)
    10.546 ± 3.6488
        Cycle 1 Day 8, 168 Hours Post-Dose (n=43)
    5.252 ± 1.7703
        Cycle 1 Day 15, 336 Hours Post-Dose (n=37)
    2.958 ± 1.1577
        Cycle 2 Day 1, Pre-Dose (n=37)
    1.668 ± 0.7608
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=37)
    35.963 ± 10.9226
        Cycle 2 Day 1, 4 Hours Post-Dose (n=37)
    32.134 ± 9.7822
        Cycle 2 Day 3, 48 Hours Post-Dose (n=35)
    14.194 ± 4.8398
        Cycle 2 Day 4, 72 Hours Post-Dose (n=32)
    10.948 ± 4.2741
        Cycle 2 Day 8, 168 Hours Post-Dose (n=34)
    6.312 ± 2.7008
        Cycle 2 Day 15, 336 Hours Post-Dose (n=27)
    3.923 ± 1.7465
        Cycle 3 Day 1, Pre-Dose (n=9)
    2.654 ± 1.0757
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=9)
    39.5 ± 6.058
        Cycle 3 Day 1, 4 Hours Post-Dose (n=9)
    37.549 ± 8.2628
        Cycle 3 Day 3, 48 Hours Post-Dose (n=8)
    19.181 ± 3.726
        Cycle 3 Day 4, 72 Hours Post-Dose (n=8)
    15.808 ± 2.0101
        Cycle 3 Day 8, 168 Hours Post-Dose (n=7)
    6.631 ± 3.8091
        Cycle 3 Day 15, 336 Hours Post-Dose (n=7)
    5.279 ± 1.9171
        Cycle 4 Day 1, Pre-Dose (n=7)
    3.252 ± 1.3859
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=7)
    42.194 ± 8.8085
        Cycle 5 Day 1, Pre-Dose (n=5)
    2.734 ± 1.2045
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=5)
    44.244 ± 27.1286
        Cycle 6 Day 1, Pre-Dose (n=5)
    2.854 ± 1.7255
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=5)
    36.304 ± 12.1646
        Cycle 6 Day 4, 72 Hours Post-Dose (n=5)
    12.667 ± 3.4384
        Cycle 6 Day 8, 168 Hours Post-Dose (n=5)
    8.04 ± 3.1264
        Cycle 7 Day 1, Pre-Dose (n=2)
    1.997 ± 0.7877
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=2)
    37.13 ± 4.9922
        Cycle 8 Day 1, Pre-Dose (n=2)
    1.901 ± 0.5834
        Cycle 8 Day 1, 10 Minute Post-Dose (n=2)
    66.24 ± 43.7558
        Cycle 9 Day 1, Pre-Dose (n=2)
    1.462 ± 0.4547
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    34.79 ± 2.0789
        Cycle 10 Day 1, Pre-Dose (n=1)
    1.282 ± 0
        Cycle 10 Day 1, 10 Minutes Post-Dose (n=1)
    26.32 ± 0
        End of Treatment (n=27)
    2 ± 1.248
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Reduction from Baseline in Tumor Size

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    End point title
    Percentage of Participants with Reduction from Baseline in Tumor Size
    End point description
    The percentage of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated
    End point type
    Secondary
    End point timeframe
    Day 21 of each 21-day cycle, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Approximately 13.9 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    10
    15
    15
    Units: percentage of participants
    50
    64
    73
    No statistical analyses for this end point

    Secondary: Number of Participants with Antitherapeutic Antibodies (ATA)

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    End point title
    Number of Participants with Antitherapeutic Antibodies (ATA)
    End point description
    Blood samples were collected to assess the immunogenicity of MLN0264 (ATA development) using a laboratory test. Neutralizing ATA assessment was performed for ATA-positive samples only.
    End point type
    Secondary
    End point timeframe
    Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 7.9 months)
    End point values
    MLN0264 1.8 mg/kg (GCC Low) MLN0264 1.8 mg/kg (GCC Intermediate) MLN0264 1.8 mg/kg (GCC High)
    Number of subjects analysed
    11
    15
    17
    Units: Participants
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose through 30 days after the last dose of study drug (Up to 7.9 Months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    MLN0264 1.8 mg/kg
    Reporting group description
    MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 10 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

    Serious adverse events
    MLN0264 1.8 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 43 (44.19%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
    Additional description: One treatment-emergent death occurred during treatment and is not related.
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
    Additional description: One treatment-emergent death occurred during treatment and is not related.
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Device failure
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholangitis
    Additional description: One treatment-emergent death occurred during treatment and is not related.
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bile duct obstruction
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
    Additional description: One treatment-emergent death occurred during treatment and is not related.
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Candida sepsis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia infection
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    MLN0264 1.8 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 43 (97.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 43 (20.93%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    16 / 43 (37.21%)
         occurrences all number
    22
    Oedema peripheral
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    5
    Pain
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Pyrexia
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Anxiety
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Weight decreased
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    7
    Thrombocytopenia
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Neutropenia
         subjects affected / exposed
    10 / 43 (23.26%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Neuropathy peripheral
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    19 / 43 (44.19%)
         occurrences all number
    23
    Dry mouth
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    14 / 43 (32.56%)
         occurrences all number
    16
    Abdominal pain upper
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Dyspepsia
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    11 / 43 (25.58%)
         occurrences all number
    15
    Nausea
         subjects affected / exposed
    17 / 43 (39.53%)
         occurrences all number
    19
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 43 (13.95%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    8
    Back pain
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 43 (30.23%)
         occurrences all number
    15
    Dehydration
         subjects affected / exposed
    7 / 43 (16.28%)
         occurrences all number
    16
    Hypokalaemia
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    7
    Hyponatraemia
         subjects affected / exposed
    4 / 43 (9.30%)
         occurrences all number
    4
    Hypophosphataemia
         subjects affected / exposed
    3 / 43 (6.98%)
         occurrences all number
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 43 (11.63%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2014
    Amendment 1: The purpose of this amendment was to provide clarification and ensure consistency in the Schedule of Events.

    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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