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    Clinical Trial Results:
    A Randomized, Open-Label, Multicenter Phase II Study of Ipilimumab Retreatment Versus Chemotherapy for Subjects With Advanced Melanoma Who Progressed After Initially Achieving Disease Control With Ipilimumab Therapy

    Summary
    EudraCT number
    		 2012-003291-38
    Trial protocol
    		 DE   GB   BE   AT   IT  
    Global end of trial date
    30 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2016
    First version publication date
    30 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA184-243
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01709162
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.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
    30 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of the study is to compare overall survival in subjects with advanced melanoma receiving ipilimumab monotherapy (3 mg/kg) as re-treatment versus chemotherapy of investigator’s choice in subjects who are randomized at the time of ipilimumab re-treatment eligibility.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Mar 2013
    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
    Austria: 3
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    31
    EEA total number of subjects
    21
    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)
    16
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 17 centres in 4 countries.

    Pre-assignment
    Screening details
    		 A total of 31 subjects were enrolled in the study, out of which 23 were randomised and 22 received treatment. The subjects discontinued the study as they no longer meet the study criteria (4), withdrew consent (3), administrative reasons (1) and other reasons (1).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab
    Arm description
    		 Subjects received ipilimumab, 3 mg/kg, intravenously every 3 weeks (at Week 1, Week 4, Week 7, and Week 10) for a total of 4 doses or until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    BMS-734016
    Other name
    Yervoy
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with ipilimumab 3mg/kg intravenously via 90-minute infusion every three weeks.

    Arm title
    		 Chemotherapy
    Arm description
    		 Subjects received the investigator's choice of chemotherapy, dosed per package instructions. Chemotherapy was defined as cytotoxic or cytostatic agents or vemurafenib, but did not include immunotherapy or experimental agents.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fotemustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with fotemustine 75 mg/m^2 infusion.

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with dacarbazine 1000 mg/m^2 infusion.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with bevacizumab 10 mg/kg infusion.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with carboplatin 6 mg/kg infusion.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with paclitaxel 150/175 mg/m^2 infusion.

    Number of subjects in period 1 [1]
    		Ipilimumab Chemotherapy
    Started
    18
    5
    Receive treatment
    18
    4
    Completed
    12
    0
    Not completed
    6
    5
         Consent withdrawn by subject
    -
    1
         Disease progression
    3
    3
         Study drug toxicity
    2
    -
         Other reasons
    1
    -
         Administrative reason by sponsor
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the baseline period are different from the worldwide number enrolled in the trial, as 8 subjects were not randomised in the study due to various reasons.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipilimumab
    Reporting group description
    		 Subjects received ipilimumab, 3 mg/kg, intravenously every 3 weeks (at Week 1, Week 4, Week 7, and Week 10) for a total of 4 doses or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects received the investigator's choice of chemotherapy, dosed per package instructions. Chemotherapy was defined as cytotoxic or cytostatic agents or vemurafenib, but did not include immunotherapy or experimental agents.

    Reporting group values
    		 Ipilimumab Chemotherapy Total
    Number of subjects
    		 18 5 23
    Age categorical
    Units: Subjects
        < 65 years
    		 9 2 11
        >= 65 years
    		 9 3 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.3 ( 11.38 ) 64.2 ( 4.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 1 7
        Male
    		 12 4 16
    Race/Ethnicity
    Units: Subjects
        White
    		 18 5 23
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG is a 6-item scale used to assess disease progression, daily functioning, appropriate treatment, and prognosis. Performance status is scored on a scale ranging from 0-5, with (best score) 0=fully active and able to carry on all predisease performance without restriction and (worst score) 5=death.
    Units: Subjects
        0 scale
    		 13 5 18
        1 scale
    		 5 0 5
    Disease Stage at Study Entry
    By the American Joint Committee on Cancer staging: Stage 1=no spread to lymph nodes/organs, <1 mm thick and not ulcerated (1A) or <1 mm thick and ulcerated or 1–2 mm thick and not ulcerated (1B). Stage 2=no spread to lymph nodes (LN) or other organs, 1–2 mm thick and ulcerated or 2–4 mm thick and not ulcerated (2A) or 2–4 mm thick and ulcerated or >4 mm thick and not ulcerated (2B), or >4 mm thick and ulcerated (2C). Stage 3 (A,B,C)=any thickness, ulcerated or not, and spread to nearby LN or nearby tissue but not LN. Stage 4=spread to LN, other organs, or areas far from original tumor site.
    Units: Subjects
        Stage III
    		 1 1 2
        Stage IV
    		 17 4 21
    Response to Prior Ipilimumab Treatment
    Tumor responses were based on investigator assessment according to modified world health organization (mWHO) criteria. Criteria for target lesions: Complete response (CR) = disappearance of all target lesions. Partial response (PR) = Decrease of 50% or greater in sum of the products of diameters (SPD) relative to baseline. Progressive disease (PD) = At least 25% increase in SPD relative to nadir. Stable disease= Does not meet criteria for CR or PR, in the absence of PD. Objective response=number of subjects with best response of CR or PR.
    Units: Subjects
        Complete response/Partial response
    		 6 0 6
        Stable disease
    		 12 5 17

    End points

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    End points reporting groups
    Reporting group title
    Ipilimumab
    Reporting group description
    		 Subjects received ipilimumab, 3 mg/kg, intravenously every 3 weeks (at Week 1, Week 4, Week 7, and Week 10) for a total of 4 doses or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects received the investigator's choice of chemotherapy, dosed per package instructions. Chemotherapy was defined as cytotoxic or cytostatic agents or vemurafenib, but did not include immunotherapy or experimental agents.

    Primary: Overall Survival

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    End point title
    		 Overall Survival [1]
    End point description
    Overall survival was defined for each subject as the time between randomization and death. If a subject has not died, he or she will be censored at the time of last contact (last known alive date). The analysis was performed in all subjects who were randomised in the study.
    End point type
    Primary
    End point timeframe
    From randomisation to death or last known alive date, assessed up to 15.6 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 summary statistics was planned for this outcome measure.
    End point values
    		 Ipilimumab Chemotherapy
    Number of subjects analysed
    18
    5
    Units: Months
        median (full range (min-max))
    6.3 (3.2 to 15.6)
    3.1 (0 to 8.6)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Disease Control

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    End point title
    		 Number of Subjects With Disease Control
    End point description
    Number of subjects with Disease Control is defined per arm as the total number of randomised subjects with best overall response as complete response, partial response, or stable disease. The study was terminated early because the study would not meet its scientific objective in the predefined time-frame. Because the study ended before best overall response could be determined, no subjects were analyzed. The analysis was performed in all subjects who were randomised in the study.
    End point type
    Secondary
    End point timeframe
    Every 3 months for approximately 3.5 years after start of randomisation and then every 6 months until confirmed and documented progressive disease
    End point values
    		 Ipilimumab Chemotherapy
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Subjects
    Notes
    [2] - The study was terminated before Disease Control Rate could be determined, no subject was analysed.
    [3] - The study was terminated before Disease Control Rate could be determined, no subject was analysed.
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate

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    End point title
    		 Best Overall Response Rate
    End point description
    Best Overall Response Rate (BORR) is defined per arm as the total number of randomised subjects with a best overall response of complete response or partial response, divided by the total number of randomised subjects in the arm. The study was terminated early because the study would not meet its scientific objective in the predefined time-frame. Because the study ended before best overall response for all subjects was defined, no subject data was analyzed. The analysis was performed in all subjects who were randomised in the study.
    End point type
    Secondary
    End point timeframe
    Every 3 months for approximately 3.5 years after start of randomisation and then every 6 months until confirmed and documented progressive disease
    End point values
    		 Ipilimumab Chemotherapy
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Subjects
    Notes
    [4] - The study was terminated before best overall response could be determined, no subject was analysed.
    [5] - The study was terminated before best overall response could be determined, no subject was analysed.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs (irAEs)

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    End point title
    		 Number of Subjects With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Immune-related AEs (irAEs)
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolonged hospitalization. The analysis was performed in all subjects who received at least one dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 of treatment to 90 days after last dose (or to death date for death information)
    End point values
    		 Ipilimumab Chemotherapy
    Number of subjects analysed
    18
    4
    Units: Subjects
        Deaths
    5
    1
        Deaths within 90 days of last dose
    1
    0
        AEs leading to discontinuation
    2
    0
        SAEs
    7
    0
        Immune related AEs
    10
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 of treatment to 90 days after last dose (or to death date for death information)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Ipilimumab
    Reporting group description
    		 Subjects received ipilimumab, 3 mg/kg, intravenously by 90-minute infusion every 3 weeks (at Week 1, Week 4, Week 7, and Week 10) for a total of 4 doses or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Chemotherapy
    Reporting group description
    		 Subjects received the investigator's choice of chemotherapy, dosed per package instructions. Chemotherapy was defined as cytotoxic or cytostatic agents or vemurafenib, but did not include immunotherapy or experimental agents.

    Serious adverse events
    		 Ipilimumab Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 18 (38.89%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    5
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myopathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipilimumab Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 18 (83.33%)
    4 / 4 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    7
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 4 (50.00%)
         occurrences all number
    4
    3
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Hypoxia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumonitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood corticotrophin decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Oral dysaesthesia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pancreatitis acute
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    6 / 18 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    Diverticulum
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tongue disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Oesophagitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Haematochezia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Decubitus ulcer
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Ingrown hair
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    5
    1
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hypophysitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Muscle fatigue
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Otitis media
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2013
    • The primary endpoint of overall survival was changed from a time-point driven endpoint to an event driven endpoint as a result of a communication with a regulatory authority • The estimated accrual period was modified from 12 months to 21 months

    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.
    As planned, accrual of subjects was to be completed within 21 months. However, the projections showed that 4 to 5 years were needed. The study was terminated early because the scientific objective could not be met in the predefined time-frame.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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