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    Clinical Trial Results:
    Neoadjuvant IntraviTreal Ranibizumab treatment in high risk Ocular melanoma patients: A two stage single centre Phase II single arm study (NITRO Trial)

    Summary
    EudraCT number
    		 2011-000961-10
    Trial protocol
    		 GB  
    Global end of trial date
    29 Oct 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NITRO Protocol
    Additional study identifiers
    ISRCTN number
    		 ISRCTN35236442
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor (RLBUHT): 3921
    Sponsors
    Sponsor organisation name
    Royal Liverpool and Broadgreen Hospitals NHS Trust
    Sponsor organisation address
    Prescot Street, Liverpool, United Kingdom, L7 8XP
    Public contact
    Charlotte Rawcliffe, Liverpool Cancer Trials Unit, 0151 794 8167, C.Rawcliffe@liverpool.ac.uk
    Scientific contact
    Victoria Shaw, GCLP Labs, 0151 706 4180 , Victoria.Shaw@liverpool.ac.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
    17 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the safety and efficacy (effectiveness) of intravitreal Ranibizumab, in the neoadjuvant (before surgery) setting, in high risk ocular melanoma patients.
    Protection of trial subjects
    Each participating site should maintain appropriate medical and research records for this trial, in compliance with ICH E6 GCP, Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of subjects. Source data will be identified and documented in the NITRO Trial Monitoring Plan. Any data to be recorded directly on the CRFs (i.e. no prior electronic or written record of the data), is to be considered to be source data e.g. questionnaires. Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents Examples of these original documents, and data records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy and laboratory departments involved in the clinical trial.
    Background therapy
    		 -
    Evidence for comparator
    		 No previous clinical trial had been done in this tumour type and setting. It is not known how anti-VEGF treatment would influence uveal melanomas in vivo. Several preclinical studies suggested antiangiogenic therapies, incl. anti-VEGF targeted therapies, could have a significant clinical impact in ocular melanoma. e.g, Clark transplanted cells from the murine uveal melanoma cell line (99E1) into the right eye of athymic nude BALB/c mice, which were subsequently treated with topical anecortave acetate (an angiostatic agent that inhibits endothelial cell migration) for 28 days; tumour growth inhibition was achieved. In another study, Yang injected murine recombinant angiostatin (another endothelial cell inhibitor) into the posterior compartment of the eye of C57BL/6 using three murine ocular melanoma cell lines (Queens, B16F10 and B16LS9). That was followed by enucleation and several more adjuvant doses. The sizes of hepatic metastasis and apoptosis ratios were significantly decreased in treated mice. Kim also showed that potent VEGF blockade with VEGF-Trap caused regression of coopted vessels in a xenograft model of neuroblastoma. Holash used the same drug to treat mice implanted with several cell lines, which included a melanoma cell line (mouse B16F10.9 melanoma), to find largely avascular tumours after treatment. More recently, Chan used the tyrosine kinase inhibitor Sunitinib, which targets the VEGF receptor as well as c-kit in ten patients with metastatic uveal melanoma. One partial response was achieved and 7 patients had stable disease with a median duration of response of 3.9 months. On the basis of the above, we believe that by using the treatment window opportunity offered by the neoadjuvant period we can study the effects of angiogenesis inhibition in this rare and aggressive tumour type, collect useful clinical and pathological information before and after treatment, and perhaps offering the patients the possibility of eye and sight preserving treatments.
    Actual start date of recruitment
    01 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    3
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 7 patients were registered onto the study.

    Pre-assignment
    Screening details
    		 Patients screened = 60

    Period 1
    Period 1 title
    Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    		 Ranibizumab
    Arm description
    		 Ranibizumab
    Arm type
    		 Single arm

    Investigational medicinal product name
    Ranibizumab
    Investigational medicinal product code
    Ranibizumab
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravitreal use
    Dosage and administration details
    Ranibizumab will be administered by intravitreal injection and must be administered by a qualified Ophthalmologist. Patients will receive an initial dose of 0.5mg in 0.05ml Ranibizumab as a single intravitreal injection. Patients then receive the same dose once monthly (subject to tumour assessment) for a maximum of 6 months.

    Number of subjects in period 1
    		Ranibizumab
    Started
    7
    Completed
    0
    Not completed
    7
         Consent withdrawn by subject
    2
         Lack of efficacy
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    		 Ranibizumab

    Reporting group values
    		 Ranibizumab Total
    Number of subjects
    		 7 7
    Age categorical
    All patients must be 18 years or older
    Units: Subjects
        Adults (18-64 years)
    		 3 3
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 66 (50 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 5 5
    WHO performance status
    WHO performance status at baseline. (0,1, or 2)
    Units: Subjects
        WHO 0
    		 7 7
        WHO 1
    		 0 0
        WHO 2
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients registered into the study

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    7
    Age categorical
    All patients must be 18 years or older
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    WHO performance status
    WHO performance status at baseline. (0,1, or 2)
    Units: Subjects
        WHO 0
    7
        WHO 1
    0
        WHO 2
    0

    End points

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    End points reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    		 Ranibizumab

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients registered into the study

    Primary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    To determine response rate of intravitreal ranibizumab, in the neoadjuvant setting, in large primary ocular melanoma patients. The overall response rate is defined as: (Number achieving complete response + number achieving partial responses)/number evaluable for response at 3 months. This was to be presented with an exact 95% confidence interval. An exact one-sided test with significance level 0.05 was also to be carried out of the null-hypothesis that the response rate is less than 20%. However, conclusions about the trial will not be based solely on the results of this test and must take into account issues with recruitment. TSC minutes dated 06/11/13 confirmed that if a patient chose enuclueation before reaching 3 months they were to be classed as having progressive disease. Because of poor recruitment the final analysis is performed on only 7 patients.
    End point type
    Primary
    End point timeframe
    From registration to end of study
    End point values
    		 Ranibizumab Full Analysis Set
    Number of subjects analysed
    7
    7
    Units: Subjects
        CR
    0
    0
        PR
    0
    0
        SD
    0
    0
        PD
    7
    7
        Not Assessable
    0
    0
        Missing
    0
    0
    Statistical analysis title
    		 Estimation of complete response rate
    Comparison groups
    Ranibizumab v Full Analysis Set
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 Estimation
    Parameter type
    		 percentage
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 41
    Variability estimate
    Standard deviation
    Notes
    [1] - Estimation of the complete response rate

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Ranibizumab
    Reporting group description
    		 Ranibizumab

    Serious adverse events
    		 Ranibizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ranibizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Eye disorder
    Additional description: Other
         subjects affected / exposed
    1 / 7 (14.29%)
         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
    03 May 2013
    Amendment 3 - Change in Chief Investigator from Professor Bertil Damato to Professor Heinrich Heinmann (Approval states Amendment 1)

    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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    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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