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    Clinical Trial Results:
    Immunomodulatory effect of esomeprazole antitumoral and high-dose under neoadjuvant and adjuvant in patients with melanoma in stage III. Randomized pilot study treatment vs control

    Summary
    EudraCT number
    		 2014-000334-30
    Trial protocol
    		 IT  
    Global end of trial date
    29 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INT27/14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fondazione IRCCS ''Istituto Nazionale dei Tumori''
    Sponsor organisation address
    via G. Venezian 1, Milano, Italy, 20133
    Public contact
    Segreteria Tecnico Scientifica, Fondazione IRCCS ''IStituto Nazionale dei Tumori'' , etico@istitutotumori.mi.it
    Scientific contact
    PI: Licia Rivoltini (licia.rivoltini@istitutotumori.mi.it) Project Manager: Paola Frati, Fondazione IRCCS ''IStituto Nazionale dei Tumori'' , paola.frati@istitutotumori.mi.it
    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
    29 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of immunomodulatory and anti-tumor effect of treatment with high doses of esomeprazole in patients with metastatic melanoma
    Protection of trial subjects
    Each patient will be informed about the study and, if accepted, must sign the consent to participate. Patients will be informed of the contingencies associated with the Protocol procedures in order to provide adequate information about potential risks. However, through the adverse events monitoring, the protection of the interests and safety of the participants will be guaranteed.
    Background therapy
    		 None
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    03 Oct 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
    Italy: 109
    Worldwide total number of subjects
    109
    EEA total number of subjects
    109
    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)
    84
    From 65 to 84 years
    23
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 As for the phaseA of the study,23 stage III melanoma patients,received oral treatment with Esom prior to surgery(5-7weeks,mean:5,7).A control group of 86 patients receiving no Esom treatment for logistic reasons(interval to surgery≤5weeks) was also included(9DO/failure).PhaseB was never activated to the rapidly evolving scenario of melanoma therapy

    Pre-assignment
    Screening details
    		 Clinical data have been collected to ascertain patient eligibility;signed ICF has been obtained & blood sample for immunological studies was withdrawn.In case surgery was scheduled at a≥5weeks interval,enrolment into the ESOM pre-surgery treatment study arm was proposed.For surgery planned before 5weeks, pts were offered to enter the Control Group

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Esom Group (treatment)
    Arm description
    		 The Esom treatment arm foreseen the administration of Esom to stage III melanoma patients undergoing lymph node surgical dissection. The treatment was given in the interval prior to surgery for a period ranging from 5 to 7 weeks, depending on the individual patients’ waiting list. Patients enrolled in this group were 23, 20 of which completed the whole treatment program.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esomeprazole
    Investigational medicinal product code
    034972416/M(40mg)
    Other name
    Nexium
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients enrolled in the Esom arm received Esom orally according to an intermittent schedule which provided a dose of 2,5 mg/kg/die for three days, followed by a maintenance dose (20 mg/die) for four days. This weekly schedule was repeated form a mean of 5-7 weeks, up to 24 h prior to surgical intervention.

    Arm title
    		 Control Group (Control)
    Arm description
    		 A group of stage III melanoma patients (not entering the Esom group for logistic reasons, i.e. surgery scheduled before 5 weeks) was included in the study as controls to gain parallel information about blood and LN immune status in the absence of ESOM administration
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Esom Group (treatment) Control Group (Control)
    Started
    23
    86
    Completed
    20
    80
    Not completed
    3
    6
         Physician decision
    -
    6
         no treatment compliance
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 Esom Group (treatment): Esomeprazole was administrated orally according to an intermittent schedule which provided a dose of 2,5 mg/kg/die for three days, followed by a maintenance dose (20 mg/die) for four days. This weekly schedule was repeated up to 24 h before the surgical intervention. Control Group (Control): A group of stage, gender and age-matched melanoma patients (not entering the tratment group for logistic reasons) included in the study as controls to gain parallel information about blood and LN immune status in the absence of ESOM administration

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 109 109
    Age categorical
    Age > 18 years
    Units: Subjects
        Adults (18-64 years)
    		 84 84
        From 65-84 years
    		 23 23
        85 years and over
    		 2 2
    Age continuous
    Age> 18
    Units: years
        arithmetic mean (full range (min-max))
    		 52 (20 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 35 35
        Male
    		 74 74

    End points

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    End points reporting groups
    Reporting group title
    Esom Group (treatment)
    Reporting group description
    		 The Esom treatment arm foreseen the administration of Esom to stage III melanoma patients undergoing lymph node surgical dissection. The treatment was given in the interval prior to surgery for a period ranging from 5 to 7 weeks, depending on the individual patients’ waiting list. Patients enrolled in this group were 23, 20 of which completed the whole treatment program.

    Reporting group title
    Control Group (Control)
    Reporting group description
    		 A group of stage III melanoma patients (not entering the Esom group for logistic reasons, i.e. surgery scheduled before 5 weeks) was included in the study as controls to gain parallel information about blood and LN immune status in the absence of ESOM administration

    Subject analysis set title
    Primary Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patiens involved in the immunological analyses were 100, of which 20 in the Esom Group (Treatment Arm) and 80 in the Control Group (Control Arm)

    Primary: Primary_1

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    End point title
    		 Primary_1
    End point description
    The phase A of the study was successfully completed,with a high patient compliance (>90% patients adhered to the full pre-surgery treatment schedule) and good safety profile of the Esom administration (about 10% patients experienced grade 1-2 toxicity).The primary endpoints were to test the modulation of the frequency and/or function of diverse immune cell subset in peripheral blood (PB) and lymph nodes of patients receiving pre-surgery Esom, and to search for signs of reduced tumor viability (decrease in ki67 proliferation marker expression and/or mitosis, and /or increase of apoptosis)in metastatic LN.The immunoprofiling of LN cell suspension andPB immune cells showed a significant increment of cytotoxic and activated T and NK cells, indicating a boost of antitumor immunity.In contrast, cells with inhibitory functions such as monocytes, MDSC and regulatory T cells were reduced, proving a reduction in local and systemic immunosuppression.
    End point type
    Primary
    End point timeframe
    5-7 weeks
    End point values
    		 Esom Group (treatment) Control Group (Control)
    Number of subjects analysed
    20
    80
    Units: number
    20
    80
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The individual tests performed for the variables group were verified with the Hochberg procedure, to consider the multiplicity of the analysis. None of the observed significance are missed because of the adjustment procedures above mentioned.
    Comparison groups
    Esom Group (treatment) v Control Group (Control)
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.05 [2]
    Method
    		 Hochberg
    Confidence interval
    Notes
    [1] - immunomodulation
    [2] - no P-value considered

    Primary: Primary_2

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    End point title
    		 Primary_2 [3]
    End point description
    In terms of effects of the treatment on tumor viability, in patients having stage IIIC and receiving pre-surgery Esom (n=8), the expression of melanoma markers (TRP1 and gp100) was significantly lower with respect to the stage IIIc (n=15) patients of the control group, implying a inferior tumor load in metastatic LN in the group receiving Esom, either to the investigational treatment or different distribution in tumor burden among the two groups.
    End point type
    Primary
    End point timeframe
    5-7 weeks
    Notes
    [3] - 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 analyses for the second of the primary end point.
    End point values
    		 Esom Group (treatment) Control Group (Control)
    Number of subjects analysed
    20
    80
    Units: number
    20
    80
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    5-7 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    AE _Group
    Reporting group description
    		 -

    Serious adverse events
    		 AE _Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 AE _Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 20 (40.00%)
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Drowning
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Bowel movement irregularity
    Additional description: bowel alteration
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Nausea
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Nov 2016
    The phase A of the study, testing the safety and immunological effects of Esom administration in pre-surgical regimen was successfully concluded. Instead, the phase B of the study, assessing the same endpoints on the long-term Esom administration in post-surgery setting, was never activated due the rapidly changing scenario of stage III patients clinical management occurring during the Adesom2 trial. Indeed, novel drugs targeting key oncogenic pathways in melanoma (i.e. BRAF and MEK inhibitors for patients bearing BRAF mutation) or stimulating immune responses through the blocking of checkpoint inhibition (anti-CTLA4 and PD-1) were introduced in clinical testing, with multiple multicentric phase II and III trials rapidly activated in our Institution. For reasons related to this clinical competitive landscape, it was substantially impossible to continue the study and activate the phase B of the protocol.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The approval of new therapies for stage III melanoma in adjuvant setting patients completely overwhelmed the field and made any clinical testing of additional new strategies impossible to be performed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28267587
    http://www.ncbi.nlm.nih.gov/pubmed/27827921
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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