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    Clinical Trial Results:
    THE IPI – MULTIBASKET TRIAL IN ADVANCED OCULAR MELANOMA: PROSPECTIVE CLINICAL PHASE II MULTIBASKET STUDY IN OCULAR MELANOMA PATIENTS WITH ADVANCED DISEASE

    Summary
    EudraCT number
    		 2010-021946-22
    Trial protocol
    		 DE  
    Global end of trial date
    06 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Nov 2021
    First version publication date
    15 Nov 2021
    Other versions
    Summary report(s)
    		 summary csr

    Trial information

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    Trial identification
    Sponsor protocol code
    DeCOG–MM-PAL11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01355120
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Essen
    Sponsor organisation address
    Hufelandstraße 55, Essen, Germany, 45147
    Public contact
    Prof. Dr. Dirk Schadendorf, University Hospital Essen, Department of Dermatology, Hufelandstraße 55, DE-45147 Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    Scientific contact
    Prof. Dr. Dirk Schadendorf, University Hospital Essen, Department of Dermatology, Hufelandstraße 55, DE-45147 Essen, 0049 2017234342, dirk.schadendorf@uk-essen.de
    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
    06 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To further characterize efficacy of second line ipilimumab monotherapy 3mg/kg given according to the MDX010-20 protocol in a broad range of pretreated metastatic (cutaneous, mucosal, and uveal) melanoma patients with or without prior systemic treatment seen in daily clinical practice: • Overall survival rate at 12 months defined as the rate of patients alive 12 months after the date from the first study treatment for complete study population
    Protection of trial subjects
    The treatment should be conducted exactly as described in the protocol. Any protocol deviations were reported. The recommendations of Good Clinical Practice (ICH-GCP: International Conference on Harmonisation - Good Clinical Practice), valid since 17.1.1997, were observed. Pregnant or lactating female patients were excluded from study participation. Additionally, patients with an existing myocarditis were excluded from study participation; for enrolled pateents, ECG examinations at baseline ad at week 12 and in case of evidence of myocarditis (e.g. dyspnoea, functional insufficiency) before each therapy cycle were obligatory. The study treatment consisted of an induction and a re-induction part. After enrolment, all patients received a maximum of 4 cycles of ipilimumab monotherapy (3 mg/kg IV, q3 weeks) according to the completed Medarex study MDX-010-20 (induction treatment). Only patients who progressed following stable disease of >=3 months duration starting from diagnosis at week 12 tumor assessment or who had progressed following an initial response (partial or complete) assessed at week 12 could receive additional cycles of ipilimumab monotherapy (re-induction treatment). Re-treatment was not permitted for patients with experience of >= grade 3 gastrointestinal adverse events (AEs) or selected immune-related adverse events (irAE) or with disease progression following the first cycle of study medication. Investigators had to align to criteria defined in the protocol for skipping or discontinuing study treatment.
    Background therapy
    		 Concomitant therapy IL-2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; any other systemic therapy for cancer including any other experimental treatment was prohibited during study therapy. Topical or inhalational steroids were permitted for management of symptoms due to brain metastases. In case of occurrence of irAEs, clinically necessary steroid therapy was permitted. In case of infusion reactions associated with ipilimumab, premedication with diphenhydramine and acetaminophen could be given for subsequent doses of ipilimumab at the discretion of the investigator. If a patient experienced isolated drug fever, for the next dose, pretreatment with acetaminophen or non-steroidal anti-inflammatory agent at the investigator’s discretion was permitted.
    Evidence for comparator
    		 Not applicable, as this was a study with one treatment arm only.
    Actual start date of recruitment
    23 May 2011
    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
    Germany: 161
    Worldwide total number of subjects
    161
    EEA total number of subjects
    161
    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)
    85
    From 65 to 84 years
    75
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 After obtaining informed consent, screening evaluations were performed to confirm eligibiliy and to obtain baseline safety data. From 23-May-2011 (first patient in) up to 21-Sep-2012 (last patient in), 161 patients were registered by 25 hospitals in Germany.

    Pre-assignment
    Screening details
    		 The selection of patients occurred by the investigators according to the inclusion and exclusion criteria. After having informed the patient orally and in writiing about the study and after obtaining the patient’s informed consent. Study treatment should begin within 14 days after registration.

    Pre-assignment period milestones
    Number of subjects started
    		 171 [1]
    Intermediate milestone: Number of subjects
    Screening: 171
    Intermediate milestone: Number of subjects
    Registration: 161
    Intermediate milestone: Number of subjects
    Treatment: 156
    Number of subjects completed
    		 156

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 13
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 171 patients have been screened, however due to not fuulfilling all aligibility criteria, only 161 patients could be enrolled.
    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Arm title
    		 Treatment
    Arm description
    		 ipilimumab monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    L01XC11
    Other name
    YERVOY
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg ipilimumab administered as iv infusion, q3weeks

    Number of subjects in period 1 [2]
    		Treatment
    Started
    156
    Completed
    156
    Notes
    [2] - 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: 156 patients received study treatment. Of the 161 enrolled patients, 5 patients were identified as screening failuire after enrolment or withdrew the indormed consent before receiving any study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 All enrolled patients who received at least one dose of study medication

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 156 156
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of registration minus year of birth.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 80 80
        From 65-84 years
    		 75 75
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (29 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 89 89
        Male
    		 67 67
    Type of melanoma
    Patients with cutaneous, mucosal, unknown primnary or ocular melanoma
    Units: Subjects
        Cutaneous
    		 83 83
        Mucosal
    		 7 7
        MUP
    		 13 13
        Ocular
    		 53 53
    LDH at baseline
    Units: Subjects
        LDH <2 ULN
    		 116 116
        LDH >=2 ULN
    		 40 40
    B-RAF mutation
    Units: Subjects
        not mutated
    		 49 49
        mutated
    		 23 23
        not known
    		 84 84
    Subject analysis sets

    Subject analysis set title
    Treated patients_total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who were enrolled and received at least one dose of ipilimumab.

    Subject analysis set title
    Response-evaluable set_total
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of ocular, cutaneous, mucosal melanoma or melanoma of unkown primary; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Treated patients_cutaneous melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'cutaneous melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Treated patients_mucosal melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'mucosal melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Treated patients_ocular melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'ocular melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Response-evaluable set_cutaneous melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of cutaneous melanoma ; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_mucosal melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of mucosal melanoma ; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_MUP
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of melanoma of unkown primary; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_ocular melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of ocular; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Treated patients_MUP
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'melanoma of unknown primary' who received at least one dose of ipilimumab.

    Subject analysis sets values
    		 Treated patients_total Response-evaluable set_total Treated patients_cutaneous melanoma Treated patients_mucosal melanoma Treated patients_ocular melanoma Response-evaluable set_cutaneous melanoma Response-evaluable set_mucosal melanoma Response-evaluable set_MUP Response-evaluable set_ocular melanoma Treated patients_MUP
    Number of subjects
    156
    104
    83
    7
    53
    55
    6
    9
    34
    13
    Age categorical
    Patients aged 18 years or older could be enrolled. There was no maximum age limit. Age was calculated as Year of registration minus year of birth.
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    80
        From 65-84 years
    75
        85 years and over
    1
    Age continuous
    Units: years
        median (full range (min-max))
    63 (29 to 85)
    65.50 (30 to 85)
    63 (29 to 85)
    63 (33 to 73)
    67 (34 to 84)
    63 (30 to 85)
    63.5 (33 to 73)
    68 (40 to 77)
    67 (36 to 84)
    62 (40 to 77)
    Gender categorical
    Units: Subjects
        Female
    67
    46
    30
    5
    30
    21
    4
    2
    19
    2
        Male
    89
    58
    53
    2
    23
    34
    2
    7
    15
    11
    Type of melanoma
    Patients with cutaneous, mucosal, unknown primnary or ocular melanoma
    Units: Subjects
        Cutaneous
    83
    55
    83
    0
    0
    55
    0
    0
    0
    0
        Mucosal
    7
    6
    0
    7
    0
    0
    6
    0
    0
    0
        MUP
    13
    9
    0
    0
    0
    0
    0
    9
    0
    13
        Ocular
    53
    34
    0
    0
    53
    0
    0
    0
    34
    0
    LDH at baseline
    Units: Subjects
        LDH <2 ULN
    116
    90
    67
    5
    33
    50
    5
    8
    26
    11
        LDH >=2 ULN
    40
    14
    16
    2
    20
    5
    1
    1
    8
    2
    B-RAF mutation
    Units: Subjects
        not mutated
    49
    30
    29
    3
    12
    17
    2
    4
    7
    5
        mutated
    23
    16
    17
    0
    0
    12
    0
    4
    0
    6
        not known
    84
    58
    37
    4
    41
    26
    4
    1
    27
    2

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 ipilimumab monotherapy

    Subject analysis set title
    Treated patients_total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who were enrolled and received at least one dose of ipilimumab.

    Subject analysis set title
    Response-evaluable set_total
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of ocular, cutaneous, mucosal melanoma or melanoma of unkown primary; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Treated patients_cutaneous melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'cutaneous melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Treated patients_mucosal melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'mucosal melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Treated patients_ocular melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'ocular melanoma' who received at least one dose of ipilimumab.

    Subject analysis set title
    Response-evaluable set_cutaneous melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of cutaneous melanoma ; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_mucosal melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of mucosal melanoma ; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_MUP
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of melanoma of unkown primary; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Response-evaluable set_ocular melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients who received at least one dose of ipilimumab with i) measurable disease at baseline determined by irRC and RECIST; ii) histologic diagnosis of ocular; and iii) who had one baseline screening and at least one tumor assessment on study

    Subject analysis set title
    Treated patients_MUP
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All enrolled patients with diagnosis 'melanoma of unknown primary' who received at least one dose of ipilimumab.

    Primary: Overall survival rate at 12 months

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    End point title
    		 Overall survival rate at 12 months [1]
    End point description
    Proportion of patients being alive or with unknown survival status 12 months after first administration of the study treatment, calculated by Kaplan Meier analysis.
    End point type
    Primary
    End point timeframe
    12 months after the date from the first study treatment
    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: No statistical analysis for the primary endpoint (= Overall survival rate at 12 months) has been specified in the protocol or the statistical analysis plan.
    End point values
    		 Treated patients_total
    Number of subjects analysed
    155
    Units: Subjects
    102
    No statistical analyses for this end point

    Secondary: Overall response rate according to immune-related response criteria (ir-RC)

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    End point title
    		 Overall response rate according to immune-related response criteria (ir-RC)
    End point description
    Proportion of patients with PR+CR as best response according to irRECIST-criteria. Any subject with irRECIST will be included in the denominator for irORR.
    End point type
    Secondary
    End point timeframe
    Evey 12 weeks during treatment and every 3 months during Follow-up phase
    End point values
    		 Response-evaluable set_total
    Number of subjects analysed
    48
    Units: Subjects
    7
    No statistical analyses for this end point

    Secondary: Overall response rate (RECIST criteria)

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    End point title
    		 Overall response rate (RECIST criteria)
    End point description
    Proportion of patients with PR+CR as best response. Any subject of the response-evaluable population will be included in the denominator for ORR.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks during treatment and every 3 months during Follow-up
    End point values
    		 Response-evaluable set_total
    Number of subjects analysed
    104
    Units: Subjects
    11
    No statistical analyses for this end point

    Secondary: Disease control rate (irRECIST)

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    End point title
    		 Disease control rate (irRECIST)
    End point description
    Proportion of patients with PR+CR+SD as best response according to irRECIST. Any subject with irRECIST will be included in the denominator for irDCR.
    End point type
    Secondary
    End point timeframe
    Staging examinations should be performed every 12 weeks during treatment and every 3 months during follow-up period
    End point values
    		 Response-evaluable set_total
    Number of subjects analysed
    48
    Units: Subjects
    22
    No statistical analyses for this end point

    Secondary: Disease control rate (RECIST)

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    End point title
    		 Disease control rate (RECIST)
    End point description
    Proportion of patients with PR+CR+SD as best response according to RECIST. Any subject of the response-evaluable population will be included in the denominator for DCR.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks during treatment and every 3 months during Follow-up
    End point values
    		 Response-evaluable set_total
    Number of subjects analysed
    104
    Units: Subjects
    37
    No statistical analyses for this end point

    Secondary: PFS rate at 6 months

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    End point title
    		 PFS rate at 6 months
    End point description
    Proportion of patients being alive or with unknown survival status and without progress or not known to progress 6 months after their first administration of the study treatment, calculated by Kaplan-Meier.
    End point type
    Secondary
    End point timeframe
    6 months after first administration of study treatment.
    End point values
    		 Treated patients_total
    Number of subjects analysed
    156
    Units: Subjects
    126
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS) was measured from the date of the first ipilimumab dose given on-study until date of death. Survival time for subjects, whose date of death is unknown, were censored at the date of last contact. Overall survival was analysed by the Kaplan Meier method
    End point type
    Secondary
    End point timeframe
    From start of study treatment until death of patient or end of study whichever occurred first.
    End point values
    		 Treated patients_total
    Number of subjects analysed
    155
    Units: months
        median (confidence interval 95%)
    6.91 (5.66 to 8.62)
    No statistical analyses for this end point

    Secondary: PFS

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    End point title
    		 PFS
    End point description
    Progression was determined according to RECIST v1.1 criteria by the respective trial sites. Progression-free survival was calculated by Kaplan-Meier-Analysis. For patients without progress and not known to have died, PFS time was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    From start of study therapy until progression or death of any cause, whatever occurred first.
    End point values
    		 Treated patients_total
    Number of subjects analysed
    156
    Units: Months
        median (confidence interval 95%)
    2.6 (2.53 to 2.73)
    No statistical analyses for this end point

    Secondary: Overall survival rate at 12 months according to type of melanoma

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    End point title
    		 Overall survival rate at 12 months according to type of melanoma
    End point description
    Proportion of patients being alive or with unknown survival status 12 months after first administration of the study treatment, calculated by Kaplan Meier method, analyzed per type of melanoma
    End point type
    Secondary
    End point timeframe
    12 months after the date from the first study treatment
    End point values
    		 Treated patients_cutaneous melanoma Treated patients_mucosal melanoma Treated patients_ocular melanoma Treated patients_MUP
    Number of subjects analysed
    83
    7
    53
    12
    Units: Subjects
    49
    6
    40
    7
    Statistical analysis title
    		 OS rate at 12 months by type of melanoma
    Comparison groups
    Treated patients_mucosal melanoma v Treated patients_cutaneous melanoma v Treated patients_ocular melanoma v Treated patients_MUP
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.58 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - No significant differnce between the types of primary melanoma

    Secondary: ORR (RECIST) according to melanoma type

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    End point title
    		 ORR (RECIST) according to melanoma type
    End point description
    Proportion of patients according to type of melanoma with PR+CR as best response.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks during treatment and every 3 months during Follow-up
    End point values
    		 Response-evaluable set_cutaneous melanoma Response-evaluable set_mucosal melanoma Response-evaluable set_MUP Response-evaluable set_ocular melanoma
    Number of subjects analysed
    55
    6
    9
    34
    Units: Subjects
    9
    1
    1
    0
    Statistical analysis title
    		 ORR (RECIST) by type of melanoma
    Comparison groups
    Response-evaluable set_cutaneous melanoma v Response-evaluable set_mucosal melanoma v Response-evaluable set_MUP v Response-evaluable set_ocular melanoma
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Confidence interval

    Secondary: PFS according to type of melanoma

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    End point title
    		 PFS according to type of melanoma
    End point description
    End point type
    Secondary
    End point timeframe
    From start of study therapy until progression or death of any cause, whatever occurred first, by type of melanoma
    End point values
    		 Treated patients_cutaneous melanoma Treated patients_mucosal melanoma Treated patients_ocular melanoma Treated patients_MUP
    Number of subjects analysed
    83
    7
    53
    13
    Units: months
        median (confidence interval 95%)
    2.57 (2.53 to 2.66)
    2.76 (1.51 to 5.72)
    2.83 (2.53 to 2.89)
    2.53 (2.27 to 4.05)
    Statistical analysis title
    		 PFS_by melanoma type
    Comparison groups
    Treated patients_cutaneous melanoma v Treated patients_mucosal melanoma v Treated patients_ocular melanoma v Treated patients_MUP
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.95
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: OS_according to melanoma type

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    End point title
    		 OS_according to melanoma type
    End point description
    End point type
    Secondary
    End point timeframe
    From start of study treatment until death of patient or end of study whichever occurred first.
    End point values
    		 Treated patients_cutaneous melanoma Treated patients_mucosal melanoma Treated patients_ocular melanoma Treated patients_MUP
    Number of subjects analysed
    83
    7
    53
    12
    Units: Months
        median (confidence interval 95%)
    6.78 (5.30 to 9.87)
    9.57 (1.55 to 11.05)
    6.78 (3.65 to 8.06)
    9.90 (2.27 to 9999999)
    Statistical analysis title
    		 OS_type of melanoma
    Comparison groups
    Treated patients_cutaneous melanoma v Treated patients_mucosal melanoma v Treated patients_ocular melanoma v Treated patients_MUP
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.24 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - No differences in OS between the tumor types

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs were reported from date of written informed consent until end date of treatment, for serious adverse events the time period was extended to 70 days post last treatment.
    Adverse event reporting additional description
    All AEs and SAEs, whether related to study treatment or not, should be recorded within the above mentioned time periods. Additionally, the investigator should notify the sponsor of any SAE occurring after this time period that is believed to be related to the investigational product or protocol-specified procedure.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.02
    Reporting groups
    Reporting group title
    Treated patients_total_Safety
    Reporting group description
    		 All patients who were enrolled and received at least one dose of ipilimumab.

    Serious adverse events
    		 Treated patients_total_Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    93 / 156 (59.62%)
         number of deaths (all causes)
    122
         number of deaths resulting from adverse events
    52
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to gastrointestinal tract
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    15 / 156 (9.62%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 13
    Tumour pain
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Arterial stenosis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous occlusion
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Tumour excision
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    1 / 3
    Disease progression
         subjects affected / exposed
    29 / 156 (18.59%)
         occurrences causally related to treatment / all
    0 / 30
         deaths causally related to treatment / all
    0 / 29
    Fatigue
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 156 (3.21%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Biopsy tongue
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Medication error
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial tachycardia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Aortic valve disease
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    9 / 156 (5.77%)
         occurrences causally related to treatment / all
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    14 / 156 (8.97%)
         occurrences causally related to treatment / all
    20 / 21
         deaths causally related to treatment / all
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 156 (3.21%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Hepatic pain
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Endocrine disorders
    Hypothyreodism
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treated patients_total_Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 156 (95.51%)
    Investigations
    GGT increased
         subjects affected / exposed
    5 / 156 (3.21%)
         occurrences all number
    9
    Nervous system disorders
    Insomnia
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 156 (5.77%)
         occurrences all number
    13
    General disorders and administration site conditions
    Back pain
         subjects affected / exposed
    10 / 156 (6.41%)
         occurrences all number
    12
    Dyspnoea
         subjects affected / exposed
    14 / 156 (8.97%)
         occurrences all number
    14
    Fatigue
         subjects affected / exposed
    37 / 156 (23.72%)
         occurrences all number
    42
    Fever
         subjects affected / exposed
    13 / 156 (8.33%)
         occurrences all number
    14
    Decreased appetite
         subjects affected / exposed
    8 / 156 (5.13%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    12 / 156 (7.69%)
         occurrences all number
    15
    Pain
         subjects affected / exposed
    14 / 156 (8.97%)
         occurrences all number
    16
    Pain in extremity
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences all number
    8
    Tumour pain
         subjects affected / exposed
    6 / 156 (3.85%)
         occurrences all number
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    6 / 156 (3.85%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 156 (10.26%)
         occurrences all number
    19
    Diarrhoea
         subjects affected / exposed
    44 / 156 (28.21%)
         occurrences all number
    67
    Nausea
         subjects affected / exposed
    17 / 156 (10.90%)
         occurrences all number
    20
    Stomach pain
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences all number
    7
    Vomiting
         subjects affected / exposed
    12 / 156 (7.69%)
         occurrences all number
    16
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences all number
    7
    Pruritus
         subjects affected / exposed
    21 / 156 (13.46%)
         occurrences all number
    22
    Rash maculo-papular
         subjects affected / exposed
    8 / 156 (5.13%)
         occurrences all number
    9
    Infections and infestations
    Arthralgia
         subjects affected / exposed
    7 / 156 (4.49%)
         occurrences all number
    8
    Colitis
         subjects affected / exposed
    6 / 156 (3.85%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    13 / 156 (8.33%)
         occurrences all number
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Aug 2011
    Recruitment was continued only for patients with ocular melanoma because sufficient numbers of cutaneous and mucosal melanoma patients had already been recruited. In order to allow the separate subgroup analysis as planned in the protocol for ocular melanoma it was mandatory to focus the recruitment to this patient population.

    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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