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    Clinical Trial Results:
    A Phase 2 Trial of MLN0264 in Previously Treated Patients With Metastatic or Recurrent Adenocarcinoma of the Stomach or Gastroesophageal Junction Expressing Guanylyl Cyclase C (GCC)

    Summary
    EudraCT number
    2014-000804-88
    Trial protocol
    IT   GB   ES   BE  
    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 based on QA comments from ClinicalTrials.gov.

    Trial information

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    Trial identification
    Sponsor protocol code
    C26002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02202759
    WHO universal trial number (UTN)
    U1111-1155-9023
    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 recurrent or metastatic guanylyl cyclase C (GCC)-positive adenocarcinoma of the stomach or gastroesophageal junction.
    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
    04 Aug 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: 2
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    38
    EEA total number of subjects
    16
    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)
    15
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 24 investigative sites in Belgium, Spain, United Kingdom and the United States from 04 August 2014 to 15 January 2016.

    Pre-assignment
    Screening details
    Participants with a diagnosis of metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing Guanylyl Cyclase C (GCC) 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 14 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
    Intramuscular and 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 9 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
    Intramuscular and 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 8 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
    Intramuscular and 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
    9
    15
    14
    Completed
    0
    0
    0
    Not completed
    9
    15
    14
         Study Terminated by Sponsor
    3
    3
    3
         Reason not Specified
    4
    11
    10
         Consent withdrawn by subject
    2
    1
    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 14 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 9 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 8 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
    9 15 14 38
    Age categorical
    Units: Subjects
        31 to 81 years
    9 15 14 38
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.1 ± 7.7 62.9 ± 12.78 62.9 ± 7.86 -
    Gender, Male/Female
    Units: participants
        Female
    1 5 1 7
        Male
    8 10 13 31
    Height
    Units: cm
        arithmetic mean (standard deviation)
    169.7 ± 7.49 167.8 ± 9.85 171.1 ± 9.38 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    71.51 ± 11.25 71.67 ± 17.06 72.75 ± 12.59 -
    Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    1.83 ± 0.168 1.81 ± 0.252 1.85 ± 0.201 -
    Subject analysis sets

    Subject analysis set title
    MLN0264 1.8 mg/kg
    Subject analysis set type
    Full 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 14 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
    Number of subjects
    38
    Age categorical
    Units: Subjects
        31 to 81 years
    38
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Gender, Male/Female
    Units: participants
        Female
    7
        Male
    31
    Height
    Units: cm
        arithmetic mean (standard deviation)
    ±
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    ±
    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 14 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 9 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 8 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
    Full 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 14 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 17 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
    9
    14
    13
    Units: percentage of participants
    0
    14
    0
    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. A serious adverse event (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. Relationship of each AE to study drug will be determined by the Investigator.
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after the last dose of study medication (Up to 10.7 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
    9
    15
    14
    Units: participants
        AEs
    8
    15
    14
        SAEs
    2
    5
    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
    From the first dose through 30 days after the last dose of study medication (Up to 10.7 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    38
    Units: participants
        Chemistry
    8
        Hematology
    13
        Coagulation
    24
        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
    Time Frame: 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 16.7 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
    9
    14
    13
    Units: days
        median (full range (min-max))
    40 (38 to 311)
    49 (38 to 316)
    87 (39 to 427)
    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 10.7 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    38
    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 in days from the date of first documentation of a confirmed response to the date of first documentation of disease progression. Per RECIST v1.1 for target lesions and assessed by magnetic resonance imaging (MRI) - 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
    Secondary
    End point timeframe
    From first documented response until disease progression (Up to 16.7 months)
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    2 [2]
    Units: days
        median (full range (min-max))
    45.5 (1 to 90)
    Notes
    [2] - Only two subjects had data collected due to early termination.
    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. 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 the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD and no new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) of target lesions, taking as reference the smallest sum LD since the treatment started and no new lesions. Investigator response is based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
    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 16.7 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
    9
    14
    13
    Units: percentage of participants
    11
    36
    54
    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 17 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
    9
    14
    13
    Units: days
        median (full range (min-max))
    230 (79 to 394)
    156 (49 to 505)
    206 (24 to 427)
    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
    Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
    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 [3]
    Units: μg/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [3] - No data was collected for this analysis due to early termination.
    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 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    38
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=37)
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
    37.0434 ± 9.93577
        Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
    26.047 ± 6.27538
        Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
    7.0839 ± 1.64899
        Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
    4.4939 ± 1.25657
        Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
    1.6795 ± 0.71586
        Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
    0.5778 ± 0.22063
        Cycle 2 Day 1, Pre-Dose (n=36)
    0.7466 ± 2.68737
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=36)
    32.1622 ± 9.61463
        Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
    26.0278 ± 9.43156
        Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
    7.7186 ± 2.04169
        Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
    4.914 ± 1.05592
        Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
    1.7813 ± 0.49456
        Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
    0.6959 ± 0.27579
        Cycle 3 Day 1, Pre-Dose (n=19)
    0.4905 ± 0.77805
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=19)
    31.1505 ± 8.74114
        Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
    25.1787 ± 5.49543
        Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
    6.736 ± 1.5694
        Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
    5.887 ± 3.05461
        Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
    1.5078 ± 0.48401
        Cycle 3 Day 15, 336 Hours Post-Dose (n=18)
    0.6807 ± 0.25869
        Cycle 4 Day 1, Pre-Dose (n=16)
    0.3916 ± 0.16462
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
    32.3427 ± 8.33045
        Cycle 5 Day 1, Pre-Dose (n=7)
    0.4757 ± 0.18995
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
    33.9286 ± 7.14793
        Cycle 6 Day 1, Pre-Dose (n=8)
    0.4915 ± 0.34173
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=8)
    30.385 ± 7.79913
        Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
    5.0676 ± 1.54862
        Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
    1.691 ± 0.40781
        Cycle 7 Day 1, Pre-Dose (n=3)
    0.5097 ± 0.20409
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
    31.0133 ± 8.2343
        Cycle 8 Day 1, Pre-Dose (n=3)
    0.5677 ± 0.2418
        Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
    31.6467 ± 8.93229
        Cycle 9 Day 1, Pre-Dose (n=2)
    0.929 ± 0.49639
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    32.35 ± 6.77408
        Cycle 11 Day 1, Pre-Dose (n=1)
    0.776 ± 0
        Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
    56.84 ± 0
        Cycle 12 Day 1, Pre-Dose (n=1)
    0.735 ± 0
        Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
    49.88 ± 0
        Cycle 13 Day 1, Pre-Dose (n=1)
    0.887 ± 0
        Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
    41.64 ± 0
        Cycle 14 Day 1, Pre-Dose (n=1)
    1.026 ± 0
        Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
    41.92 ± 0
        End of Treatment (n=26)
    0.3323 ± 0.21216
    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 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    38
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=37)
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
    41.8154 ± 10.05341
        Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
    35.7626 ± 8.46954
        Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
    16.0664 ± 3.26969
        Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
    11.7461 ± 2.60098
        Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
    6.1851 ± 1.73972
        Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
    3.3926 ± 1.00149
        Cycle 2 Day 1, Pre-Dose (n=36)
    2.5995 ± 3.79916
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=35)
    43.4749 ± 9.71796
        Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
    35.6691 ± 10.26134
        Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
    18.4167 ± 4.07769
        Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
    13.3398 ± 3.23987
        Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
    7.3613 ± 1.87974
        Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
    4.3511 ± 1.47322
        Cycle 3 Day 1, Pre-Dose (n=19)
    2.5274 ± 1.54088
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=19)
    41.3674 ± 11.88629
        Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
    33.2692 ± 9.4253
        Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
    15.95 ± 5.08026
        Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
    12.8393 ± 4.56059
        Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
    7.5035 ± 2.01984
        Cycle 3 Day 15, 336 Hours Post-Dose (n=18)
    4.2384 ± 1.66059
        Cycle 4 Day 1, Pre-Dose (n=16)
    2.9082 ± 1.03729
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
    45.4333 ± 13.8498
        Cycle 5 Day 1, Pre-Dose (n=7)
    3.2396 ± 0.88493
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
    43.0629 ± 7.30566
        Cycle 6 Day 1, Pre-Dose (n=8)
    3.081 ± 1.29133
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=8)
    39.93 ± 10.13066
        Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
    14.7957 ± 4.09897
        Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
    9.6217 ± 1.53148
        Cycle 7 Day 1, Pre-Dose (n=3)
    3.3417 ± 1.64015
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
    42.1667 ± 8.725528
        Cycle 8 Day 1, Pre-Dose (n=3)
    3.0573 ± 1.21148
        Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
    32.6333 ± 5.9498
        Cycle 9 Day 1, Pre-Dose (n=2)
    3.044 ± 0.98429
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    45.8 ± 7.04278
        Cycle 11 Day 1, Pre-Dose (n=1)
    4.242 ± 0
        Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
    44.3 ± 0
        Cycle 12 Day 1, Pre-Dose (n=1)
    4.102 ± 0
        Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
    47.38 ± 0
        Cycle 13 Day 1, Pre-Dose (n=1)
    4.99 ± 0
        Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
    55.26 ± 0
        Cycle 14 Day 1, Pre-Dose (n=1)
    5.675 ± 0
        Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
    61.5 ± 0
        End of Treatment (n=26)
    2.5393 ± 1.32302
    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 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.
    End point values
    MLN0264 1.8 mg/kg
    Number of subjects analysed
    38
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, Pre-Dose (n=37)
    0 ± 0
        Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
    0.473 ± 0.6503
        Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
    2.659 ± 1.5489
        Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
    6.153 ± 3.2773
        Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
    5.856 ± 3.4519
        Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
    2.945 ± 1.8899
        Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
    0.532 ± 0.6693
        Cycle 2 Day 1, Pre-Dose (n=36)
    0.116 ± 0.1118
        Cycle 2 Day 1, 10 Minutes Post-Dose (n=35)
    0.425 ± 0.2697
        Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
    2.665 ± 1.7137
        Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
    6.746 ± 4.2361
        Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
    6.111 ± 3.6283
        Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
    2.898 ± 2.2974
        Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
    0.579 ± 0.6221
        Cycle 3 Day 1, Pre-Dose (n=19)
    0.094 ± 0.124
        Cycle 3 Day 1, 10 Minutes Post-Dose (n=18)
    0.428 ± 0.4487
        Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
    2.302 ± 1.8893
        Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
    4.493 ± 2.6877
        Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
    3.638 ± 1.857
        Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
    2.135 ± 1.703
        Cycle 3 Day 15, 336 Hours Post-Dose (n=17)
    0.342 ± 0.3637
        Cycle 4 Day 1, Pre-Dose (n=16)
    0.081 ± 0.0865
        Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
    0.304 ± 0.1781
        Cycle 5 Day 1, Pre-Dose (n=7)
    0.084 ± 0.0331
        Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
    0.278 ± 0.1325
        Cycle 6 Day 1, Pre-Dose (n=8)
    0.093 ± 0.0654
        Cycle 6 Day 1, 10 Minutes Post-Dose (n=7)
    0.322 ± 0.2232
        Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
    6.183 ± 3.3587
        Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
    2.417 ± 1.6379
        Cycle 7 Day 1, Pre-Dose (n=3)
    0.044 ± 0.0083
        Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
    0.115 ± 0.0439
        Cycle 8 Day 1, Pre-Dose (n=3)
    0.058 ± 0.0103
        Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
    0.132 ± 0.0425
        Cycle 9 Day 1, Pre-Dose (n=2)
    0.021 ± 0.0291
        Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
    0.158 ± 0.0721
        Cycle 11 Day 1, Pre-Dose (n=1)
    0.093 ± 0
        Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
    0.186 ± 0
        Cycle 12 Day 1, Pre-Dose (n=1)
    0.087 ± 0
        Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
    0.167 ± 0
        Cycle 13 Day 1, Pre-Dose (n=1)
    0.074 ± 0
        Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
    0.132 ± 0
        Cycle 14 Day 1, Pre-Dose (n=1)
    0.081 ± 0
        Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
    0.165 ± 0
        End of Treatment (n=25)
    0.173 ± 0.3359
    No statistical analyses for this end point

    Secondary: Number of Participants With Reduction From Baseline in Tumor Size

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    End point title
    Number of Participants With Reduction From Baseline in Tumor Size
    End point description
    The number 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 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 16.7 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
    9
    14
    13
    Units: participants
    1
    2
    4
    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
    Analysis of GCC protein expression levels in tumor tissue (fresh biopsy pretreatment and whenever a biopsy is considered medically safe and technically feasible) was performed using a semiquantitative immunohistochemistry (IHC) assay and the total GCC H-Score was determined. 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 was required to obtain archival tumor specimens for GCC expression assessment prior to screening.
    End point type
    Secondary
    End point timeframe
    Approximately 20 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
    9
    15
    14
    Units: scores on a scale
        arithmetic mean (full range (min-max))
    74.8 (27 to 100)
    154.6 (110 to 230)
    344.3 (260 to 480)
    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 10.7 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
    9
    15
    14
    Units: participants
    0
    3
    1
    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 10.7 Months)
    Adverse event reporting additional description
    At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of 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 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 14 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
    7 / 38 (18.42%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
    Additional description: One treatment-emergent death occurred during treatment with MLN0264 with and is not related.
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Tumour hemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    MLN0264 1.8 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 38 (97.37%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 38 (26.32%)
         occurrences all number
    16
    Fatigue
         subjects affected / exposed
    12 / 38 (31.58%)
         occurrences all number
    14
    Pain
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    7 / 38 (18.42%)
         occurrences all number
    8
    Pyrexia
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Confusional state
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Weight decreased
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    4
    Neutrophil count decreased
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 38 (13.16%)
         occurrences all number
    6
    Anaemia
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    4
    Orthopnoea
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Tremor
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Neuropathy peripheral
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    6
    Hypoaesthesia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    9 / 38 (23.68%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    6 / 38 (15.79%)
         occurrences all number
    7
    Dysphagia
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Ascites
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    20 / 38 (52.63%)
         occurrences all number
    30
    Stomatitis
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    10 / 38 (26.32%)
         occurrences all number
    13
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 38 (13.16%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    3
    Decreased appetite
         subjects affected / exposed
    11 / 38 (28.95%)
         occurrences all number
    13
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    5
    Hyperglycaemia
         subjects affected / exposed
    3 / 38 (7.89%)
         occurrences all number
    4
    Hypocalcaemia
         subjects affected / exposed
    4 / 38 (10.53%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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
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