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    Clinical Trial Results:
    SONATINA: A Phase II Multi-Centre Randomised Controlled Study of Nelfinavir Addition to Radiotherapy Treatment in Neo-Adjuvant Therapy for Rectal Cancer

    Summary
    EudraCT number
    2010-020621-40
    Trial protocol
    GB  
    Global end of trial date
    20 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Jul 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO_021
    Additional study identifiers
    ISRCTN number
    ISRCTN29580179
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Clinical Trials and Research Governance, Joint Research Office, Block 60, Churchill Hosp, Old Road , Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    University of Oxford, University of Oxford, 44 1865 572224, ctrg@admin.ox.ac.uk
    Scientific contact
    University of Oxford, University of Oxford, 44 1865 572224, ctrg@admin.ox.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
    10 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the activity of the drug, Nelfinavir, when it is used to sensitise rectal cancer to radiotherapy treatment to try to make the radiotherapy more effective.
    Protection of trial subjects
    The trial received ethical and regulatory approval, and was run in compliance with the Medicines for Human Use (Clinical Trials) Regulations 2004, and amendments thereafter, the guidelines for Good Clinical Practice, and the applicable policies of the Sponsor, the University of Oxford. Together, these regulations implement the ethical principles of the Declaration of Helsinki (2008) and the regulatory requirements for clinical trials of an investigational medicinal product as set out in the European Union (EU) Directives 2001/20/EC (Clinical Trials) and 2005/28/EC (GCP). Patients also were seen for study assessments every 4 weeks from their last day of radiotherapy for 5 months as consistent with standard NHS therapy.
    Background therapy
    No other background therapies/treatments used.
    Evidence for comparator
    No comparator used - single arm study.
    Actual start date of recruitment
    05 Apr 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    6 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: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    5
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment was open from April 2011 until January 2014. 8 patients were recruited from a single centre to assess safety prior to extending to the multi-centre randomised trial, and this was then extended to 16 patients. However, because recruitment targets were not met, the study was terminated early with only 10 patients recruited.

    Pre-assignment
    Screening details
    19 patients were screened, of which 9 were ineligible. 2 patients had a performance status of 3 (eligibility criteria required 0-2), 3 patients were suitable for alternative trials, one patient's primary tumour was not symptomatic, one patient had impaired memory, one patient declined & for one patient the MDT did not feel SCRT was appropriate.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Baseline
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Nelfinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nelfinavir was administered orally 1250mg bd from day-7 (7 days before RT commences on day 1) to day 7 (the last day of RT). Radiotherapy was delivered in fractions of 5 Gy daily from day 1 to day 7. Total dose of radiotherapy is 25 Gy prescribed to the ICRU reference point. Radiotherapy technique could be 3D-conformal or IMRT.

    Number of subjects in period 1
    Baseline
    Started
    10
    Completed
    10
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Nelfinavir + radiotherapy
    Arm description
    When the trial had been halted for an interim analysis, the decision to extend the initial safety cohort from 8 patients to 16 patients was made, before the decision was made to close the trial early due to slow recruitment. Therefore all the patients in this arm (the safety cohort) received the Nelfinavir + short course radiotherapy (SCRT).
    Arm type
    Experimental

    Investigational medicinal product name
    Nelfinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nelfinavir was administered orally 1250mg bd from day-7 (7 days before RT commences on day 1) to day 7 (the last day of RT). Radiotherapy was delivered in fractions of 5 Gy daily from day 1 to day 7. Total dose of radiotherapy is 25 Gy prescribed to the ICRU reference point. Radiotherapy technique could be 3D-conformal or IMRT.

    Number of subjects in period 2
    Nelfinavir + radiotherapy
    Started
    10
    Completed
    8
    Not completed
    2
         Adverse event, non-fatal
    2

    Baseline characteristics

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

    Reporting group values
    Baseline Total
    Number of subjects
    10 10
    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)
    5 5
        From 65-84 years
    5 5
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    5 5
        Male
    5 5
    ECOG performance status
    Units: Subjects
        PS 0
    4 4
        PS 1
    6 6
    Rectal sub-site of target lesion
    Units: Subjects
        Low
    7 7
        Low to Mid
    1 1
        Mid
    1 1
        Mid to Upper
    1 1
    Extramural vascular invasion (EMVI)
    Units: Subjects
        Yes
    5 5
        No
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    -
    Reporting group title
    Nelfinavir + radiotherapy
    Reporting group description
    When the trial had been halted for an interim analysis, the decision to extend the initial safety cohort from 8 patients to 16 patients was made, before the decision was made to close the trial early due to slow recruitment. Therefore all the patients in this arm (the safety cohort) received the Nelfinavir + short course radiotherapy (SCRT).

    Primary: Incidence of any CTCAE grade 3 or higher toxicities

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    End point title
    Incidence of any CTCAE grade 3 or higher toxicities [1]
    End point description
    The primary outcome for the SONATINA safety cohort analysis is safety measured by incidence of any grade 3 or higher non-haematological or haematological toxicity (according to CTCAE v 4.0) up to 28 days post-SCRT. Toxicities that occurred up to 28 days post-SCRT have been summarised by Adverse Event Term. No formal comparison has been made as there is only one treatment arm.
    End point type
    Primary
    End point timeframe
    Up to 28 days post the last day of radiotherapy 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: The primary outcome for the SONATINA safety cohort analysis was safety measured by incidence of any grade 3 or higher non-haematological or haematological toxicity (according to CTCAE v 4.0) up to 28 days post-SCRT. Toxicities that occurred up to 28 days post-SCRT have been summarised. No formal comparison has been made as there is only one treatment arm.
    End point values
    Nelfinavir + radiotherapy
    Number of subjects analysed
    10
    Units: CTCAE grade 3 or higher toxicity
        Grade 3 Drug Reaction
    1
        Grade 3 Diarrhoea
    2
        Grade 3 Peri-Anal Pain
    1
        Grade 3 Lymphopenia
    2
        Grade 3 Hyponatremia
    1
        Grade 3 Vomiting
    1
    No statistical analyses for this end point

    Primary: TCD in biopsy taken 7 days from last fraction of protocol radiotherapy.

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    End point title
    TCD in biopsy taken 7 days from last fraction of protocol radiotherapy. [2]
    End point description
    The primary aim of the main SONATINA trial was to investigate the effect of Nelfinavir (the study drug) added to short-course radiotherapy in improving response rate in patients with rectal cancer patients, whilst testing the feasibility of using Tumour Cell Density (TCD) in the primary tumour to measure response rate. The primary tumour TCD of each patient was measured before and after their Nelfinavir and SCRT treatment.
    End point type
    Primary
    End point timeframe
    Before and after the Nelfinavir and SCRT treatment
    Notes
    [2] - 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: The primary outcome for the SONATINA trial (before it was closed due to slow recruitment) was Tumour Cell Density (TCD) in primary tumour biopsy taken 7 days from last faction of SCRT. No formal comparison has been made as there is only one treatment arm, and only a very small number of patients.
    End point values
    Nelfinavir + radiotherapy
    Number of subjects analysed
    9 [3]
    Units: Tumour Cell Density (% Tumour)
    median (inter-quartile range (Q1-Q3))
        Pre-treatment TCD (% Tumour)
    24.3 (13.4 to 44.5)
        Post-treatment TCD (% Tumour)
    9.2 (3.3 to 16.3)
        Difference pre to post treat (% Tumour)
    15.1 (10.1 to 28.2)
    Attachments
    TCD comparison: Pre to Post SCRT
    Notes
    [3] - One patient had no tumour in their post treatment biopsy
    No statistical analyses for this end point

    Secondary: Radiological response of primary tumour at 8 weeks post SCRT evaluated by RECIST

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    End point title
    Radiological response of primary tumour at 8 weeks post SCRT evaluated by RECIST
    End point description
    Radiological response evaluated by RECIST (version 1.1) assessment of primary tumour on MRI at 8 weeks post-SCRT. 8 out of 10 patients (80%) can be classed as responders, as they had Complete Response, Partial Response or Stable Disease at 8 weeks. Patient ST1002 had Progressive Disease at 8 weeks, and ST1010 is Not Evaluable as they had died before the 8 week assessment, so these two patients are classed as non-responders.
    End point type
    Secondary
    End point timeframe
    8 weeks post short course radiotherapy (SCRT) treatment
    End point values
    Nelfinavir + radiotherapy
    Number of subjects analysed
    9 [4]
    Units: Patients
        Complete Response
    3
        Partial Response
    4
        Stable Disease
    1
        Progressive Disease
    1
    Notes
    [4] - One patient died before their 8 week scan
    No statistical analyses for this end point

    Secondary: Radiological response of primary tumour at 8 weeks post SCRT evaluated by mrTRG assessment

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    End point title
    Radiological response of primary tumour at 8 weeks post SCRT evaluated by mrTRG assessment
    End point description
    Radiological response evaluated by mrTRG assessment of primary tumour on MRI at 8 weeks post-SCRT. As well as being assessed with RECIST criteria, the patients’ primary tumours were also assessed using mrTRG scores by two radiologists. If the two radiologists did not agree in their assessment, there was a third radiologist’s opinion. The overall mrTRG score that was assigned to each patient is presented. 5/9 (56%) of the mrTRG assessed SONATINA patients’ primary tumours were classed as good overall by the radiologists.
    End point type
    Secondary
    End point timeframe
    8 weeks post short course radiotherapy (SCRT) treatment.
    End point values
    Nelfinavir + radiotherapy
    Number of subjects analysed
    9 [5]
    Units: Patients
        Good mrTRG assessment
    5
        Poor mrTRG assessment
    4
    Notes
    [5] - One patient died before their 8 week scan
    No statistical analyses for this end point

    Secondary: Proportion of patients proceeding to resectional pelvic surgery

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    End point title
    Proportion of patients proceeding to resectional pelvic surgery
    End point description
    The proportion of SONATINA patients proceeding to pelvic surgery within 6 months from last fraction of radiotherapy. No SONATINA patients proceeded to have pelvic surgery within 6 months of their radiotherapy treatment.
    End point type
    Secondary
    End point timeframe
    Within 6 months from last fraction of short course radiotherapy (SCRT)
    End point values
    Nelfinavir + radiotherapy
    Number of subjects analysed
    10
    Units: Patients
        Proceeded to pelvic surgery
    0
        Did not proceed to pelvic surgery
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 6 months post-SCRT
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Nelfinivir + radiotherapy
    Reporting group description
    Nelfinavir + radiotherapy

    Serious adverse events
    Nelfinivir + radiotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Nelfinivir + radiotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Lymphopenia
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    6
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Sensory peripheral neuropathy
    Additional description: Cold induced sensory peripheral neuropathy
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Bilateral Paresthesia
    Additional description: Bilateral Paresthesia - hands
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Eye disorders
    Burst blood vessel
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 10 (70.00%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Extravasation of CT contrast
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Dizzy and confused after scan
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Drug reaction
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Bleeding during biopsy
    Additional description: Minor bleeding during biopsy
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Labyrinthitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Anal pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Bloating
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    6 / 10 (60.00%)
         occurrences all number
    15
    Flatulence
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    7
    Per rectal bleeding
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Perianal discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Perianal pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Proctitis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    3
    Stomach cramps
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    6
    Renal and urinary disorders
    Urinary incontinence
    Additional description: Urinary symptoms; frequency, urgency and incontinence
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    3
    Dysuria
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Tenesmus
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Prostatism
    Additional description: Prostatism (cystitis noninfective)
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Vaginal pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Dry macular skin rash
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Radiation skin injury
    Additional description: Radiation skin reaction
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Erythema
    Additional description: Skin erythema - natal cleft
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Trismus
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Left flank pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia and bulimia syndrome
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Low appetite
         subjects affected / exposed
    1 / 10 (10.00%)
         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
    14 Jun 2012
    The main purpose of this amendment was to clarify the definition of the safety cohort and to amend the definition of end of trial.
    17 Sep 2012
    The main purpose of this amendment was to expand the safety cohort from 8 to 16 patients since the levels of grade 3/4 toxicity experienced were slightly, but not significantly, higher than one would expect from radiotherapy alone. So we needed to study more patients in order to be able to tell whether there is any significant toxicity from the combination of radiotherapy and Nelfinavir being tested in this trial.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Jan 2014
    Early trial termination submitted 20 January 2014. The justification for premature end of the trial was: due to insufficient recruitment (SONATINA protocol section 11.1 states ‘Recruitment rate should average 1-2 patients per month per site in order to accrue to the projected accrual target within 24 months’), whereas In the last 12 month period, the recruitment rate has been 0.16 patients recruited per month, it is therefore not feasible to continue the trial
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination due to slow recruitment leading to a very small number of subjects analysed
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