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    Clinical Trial Results:
    A Phase II Trial of Metformin and Axitinib in BRAF Mutated Advanced Melanoma

    Summary
    EudraCT number
    		 2011-001793-26
    Trial protocol
    		 GB  
    Global end of trial date
    29 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2019
    First version publication date
    28 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3590
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Fulham Road, London, United Kingdom, SW36JJ
    Public contact
    Lyra Del Rosario, The Royal Marsden NHS Foundation Trust, +44 2078082710, Lyra.DelRosario@rmh.nhs.uk
    Scientific contact
    Lyra Del Rosario, The Royal Marsden NHS Foundation Trust, +44 2078082710, Lyra.DelRosario@rmh.nhs.uk
    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
    07 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of metformin and axitinib in BRAF mutated advanced melanoma. The secondary objectives of the study are to evaluate response rate at 12 weeks, overall survival and toxicity of treatment.
    Protection of trial subjects
    Patients are closely monitored during the study by the investigator and other delegated clinical members of the research team. Conducting regular tests and procedures to asses clinical status of the patient are written into the protocol to detect adverse events early on, minimising worsening of symptoms.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    01 Nov 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    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)
    1
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential patients were identified by the Principal Investigator, Sub-Investigators and research nurses during out-patient clinics. Patients were given trial information and adequate time (>24hrs) to consider study entry. Recruitment duration was 2 years from study opening.

    Pre-assignment
    Screening details
    		 Screening evaluations were performed to confirm eligibility. Seven (7) patients consented into the trial and 4 were screen failures. This analysis includes patients consent into the trial and had at least one dose of trial drugs. Screen failures were not included.

    Period 1
    Period 1 title
    Baseline and study treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Single arm
    Arm description
    		 This study is single-arm. All patients received metformin and axitinib, treatment continued for as long as patients are judged to be gaining clinical benefit by their clinician.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Axitinib and Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Axitinib - 5mg BD daily Metformin - 500mg bd and increased after 2 weeks to 850mg bd and after 2 further weeks to a dose of 850mg three times daily

    Number of subjects in period 1
    		Single arm
    Started
    3
    Completed
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline and study treatment
    Reporting group description
    		 -

    Reporting group values
    		 Baseline and study treatment Total
    Number of subjects
    		 3 3
    Age categorical
    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)
    		 1 1
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 66 (60 to 73) -
    Gender categorical
    Units: Subjects
        Male
    		 3 3
    Pre-treatment with BRAF inhibitor
    Patient history were checked if they have received previous BRAF inhibitor treatment.
    Units: Subjects
        Yes
    		 3 3
        No
    		 0 0
    Family history of Melanoma
    Patient history was checked if they had family history of melanoma.
    Units: Subjects
        Yes
    		 0 0
        No
    		 3 3
    Previous Radiotherapy for Melanoma
    Patient history was checked if patients received previous radiotherapy for their melanoma.
    Units: Subjects
        Yes
    		 2 2
        No
    		 1 1
    Previous anti-cancer therapy
    Patient history was checked if they receive previous anti-cancer therapy.
    Units: Subjects
        Yes
    		 3 3
        No
    		 0 0
    ECOG - performance status
    Patients' performance status was assessed at screening according to European Coorperative Oncology Group (ECOG) measurement.
    Units: Subjects
        Score 0
    		 1 1
        Score 1
    		 2 2
    ECG status
    All patients underwent Electrocardiograph (ECG) testing to check their cardiac status.
    Units: Subjects
        Normal
    		 2 2
        Abnormal (not clinically significant)
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Entire patients recruited on the study
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients recruited and received treatment is included

    Subject analysis set title
    End of study
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The patients who received Axitinib and Metformin treatments

    Subject analysis sets values
    		 Entire patients recruited on the study End of study
    Number of subjects
    3
    3
    Age categorical
    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)
    1
        From 65-84 years
    2
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    66 (60 to 73)
    Gender categorical
    Units: Subjects
        Male
    3
    Pre-treatment with BRAF inhibitor
    Patient history were checked if they have received previous BRAF inhibitor treatment.
    Units: Subjects
        Yes
    3
        No
    0
    Family history of Melanoma
    Patient history was checked if they had family history of melanoma.
    Units: Subjects
        Yes
    0
        No
    3
    Previous Radiotherapy for Melanoma
    Patient history was checked if patients received previous radiotherapy for their melanoma.
    Units: Subjects
        Yes
    2
        No
    1
    Previous anti-cancer therapy
    Patient history was checked if they receive previous anti-cancer therapy.
    Units: Subjects
        Yes
    3
        No
    0
    ECOG - performance status
    Patients' performance status was assessed at screening according to European Coorperative Oncology Group (ECOG) measurement.
    Units: Subjects
        Score 0
    1
        Score 1
    2
    ECG status
    All patients underwent Electrocardiograph (ECG) testing to check their cardiac status.
    Units: Subjects
        Normal
    2
        Abnormal (not clinically significant)
    1

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 This study is single-arm. All patients received metformin and axitinib, treatment continued for as long as patients are judged to be gaining clinical benefit by their clinician.

    Subject analysis set title
    Entire patients recruited on the study
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients recruited and received treatment is included

    Subject analysis set title
    End of study
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The patients who received Axitinib and Metformin treatments

    Primary: Proportion of patients progression free at 6 months

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    End point title
    		 Proportion of patients progression free at 6 months
    End point description
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Entire patients recruited on the study End of study
    Number of subjects analysed
    3
    3
    Units: Proportion
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Progression free survival at 6 months
    Comparison groups
    Entire patients recruited on the study v End of study
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Proportion
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [1] - Parameter estimate - Progression free survival at 6 months

    Secondary: Response at 12 weeks

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    End point title
    		 Response at 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    The response assessed by the RECIST criteria at 12 weeks.
    End point values
    		 Entire patients recruited on the study
    Number of subjects analysed
    3
    Units: Number responding to treatment
        Complete Response
    0
        Partial Response
    0
        Stable Disease
    0
        Progressive Disease
    1
        Unevaluable
    2
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Kaplan Meier method was used to calculate overall survival time (in months) from date of registration to date of death
    End point type
    Secondary
    End point timeframe
    Patients will be followed from date of registration to death from any cause
    End point values
    		 Entire patients recruited on the study
    Number of subjects analysed
    3
    Units: Overall Survival Time
        median (confidence interval 95%)
    3.5 (2.6 to 12.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events will be collected from the day of consenting to until 30 days after the last administration of the Investigational Medicinal Products.
    Adverse event reporting additional description
    Each adverse event will be reported with: onset date, time point and pre-defined expected AE categories including a free-text box for those that does not fall under any of the categories. NCI-CTCAE ver 4 is used to record the severity of each event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 This study is single-arm. All patients received metformin and axitinib, treatment continued for as long as patients are judged to be gaining clinical benefit by their clinician.

    Serious adverse events
    		 Single arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
    Additional description: There SAE was Grade 3 severity and lead to Hospitalisation or Prolongation of existing hospitalisation.
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: This SAE was Grade 4 leading to Hospitalisation or prolongation of existing hospitalisation.
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: There SAE was Grade 3 severity and lead to Hospitalisation or Prolongation of existing hospitalisation.
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Single arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue/Lethargy
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    3
    Dry mouth
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    3
    Anorexia
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acneiform
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Psychiatric disorders
    Mood alteration/anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2011
    The amendment is a recommendation by the MHRA to add amend the exclusion criteria in line with the Investigator Brochure ver 10.
    10 May 2012
    Change to the protocol and trial design include: participants will consent to BRAF testing prior to screening evaluations; addition of laboratory manual, removal of 'serum lipase and amylase' in inclusion criteria, removal of 'abstinence' as a form of contraception; exclusion criteria on washout period is updated; and administrative changes were also made. Patient information sheet updated to reflect protocol changes. Patient registration form amended.
    15 Jun 2012
    New wording added in the protocol for hypertension management guidelines. Patient information sheet updated as per protocol change and a diary card is introduced for the trial.

    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.
    The study did not meet its recruitment target but due to changes in the treatment landscape, it was deemed unethical to continue recruitment.
    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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