Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   40995   clinical trials with a EudraCT protocol, of which   6701   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Phase II Clinical Trial of 6-Mercaptopurine(6MP)and low-dose Methotrexate In Patients With Known BRCA Defective Tumours.

    Summary
    EudraCT number
    2009-016846-16
    Trial protocol
    GB  
    Global end of trial date
    16 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Mar 2018
    First version publication date
    04 Mar 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    OCTO-16
    Additional study identifiers
    ISRCTN number
    ISRCTN63150635
    US NCT number
    NCT01432145
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Clinical Trials & Research Governance, Joint Research Office, Block 60, Churchill Hospital, Old Road, Oxford, United Kingdom, OX3 7LJ
    Public contact
    Ms Heather House, Clinical Trials & Research Governance, University of Oxford , 01865 572245, heather.house@admin.ox.ac.uk
    Scientific contact
    Ms Heather House, Clinical Trials & Research Governance, University of Oxford , 01865 572245, heather.house@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
    02 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the anti-cancer activity of 6MP with low dose Methotrexate in patients with breast, ovarian, fallopian tube or primary serous peritoneal cancer and a known BRCA mutation.
    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 001/20/EC (Clinical Trials) and 2005/28/EC (GCP). Patients also were seen for study assessments up to 28 days post end of treatment and thereafter every 3 months for clinical assessment up to a total of 12 months.
    Background therapy
    BRCA1 and BRCA2 genes are critical in homologous recombination (HR) DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. In a screen for novel drugs that selectively kill BRCA-defective cells, Helleday and colleagues identified 6-thioguanine (6TG). They demonstrated that 6TG induces DNA double-strand breaks that are repaired by HR. The defect in HR explains the hypersensitivity of BRCA-defective cells to 6TG. Furthermore, this pre-clinical study showed that 6TG is as efficient as the PARP inhibitor, AG014699, in selectively killing BRCA-defective tumours in a xenograft model. Importantly, 6TG also kills cisplatin-resistant or PARP inhibitor resistant BRCA- defective cells. The findings of Helledey and colleagues suggest that 6TG/6MP might be an effective treatment in BRCA deficient tumours even after developing resistance to PARP inhibitors or platinum drugs.
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    54
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    74 patients were consented and registered from 14 UK sites between May 2011 and October 2014, and 67 of these registered patients were found to be evaluable. This is larger than the planned sample size of 65 patients, to compensate for unevaluable patients.

    Pre-assignment
    Screening details
    Over 130 patients with advanced ovarian or breast cancer were screened for eligibility from 14 UK sites between May 2011 and October 2014.

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

    Arms
    Arm title
    6MP and methotrexate
    Arm description
    6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week
    Arm type
    Experimental

    Investigational medicinal product name
    6MP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose of 6MP was 55mg/m2 body surface area, administered orally (PO) once a day (od) in the morning at least 1 hour after eating, on a continuous schedule. Tablets should have been taken at roughly the same time each day.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate (15 mg/m2) was taken orally, once a week, in the morning.

    Number of subjects in period 1
    6MP and methotrexate
    Started
    67
    Completed
    67

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    -

    Reporting group values
    Baseline Total
    Number of subjects
    67 67
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    54 54
        From 65-84 years
    13 13
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    55.9 (32 to 80) -
    Gender categorical
    Units: Subjects
        Female
    67 67
        Male
    0 0
    BRCA status
    Units: Subjects
        BRCA 1
    40 40
        BRCA 2
    27 27
    Prior PARP treatment
    Units: Subjects
        Yes
    26 26
        No
    41 41
    ECOG Performance Status
    Units: Subjects
        PS 0
    27 27
        PS 1
    36 36
        PS 2
    4 4
    Albumin levels
    Units: g/dl
        arithmetic mean (full range (min-max))
    39.8 (28 to 49) -
    TPMT
    Units: (mU/L)
        arithmetic mean (full range (min-max))
    88.3 (43 to 160) -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    6MP and methotrexate
    Reporting group description
    6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week

    Primary: Overall response rate

    Close Top of page
    End point title
    Overall response rate [1]
    End point description
    Objective response defined as complete response, partial response and stable disease as measured by radiological disease response using RECIST criteria v1.1 (Appendix 3 of the protocol) with tumour size measured radiologically with computerised tomography (CT) and/or magnetic resonance imaging (MRI) (using the same at baseline and at follow-up).
    End point type
    Primary
    End point timeframe
    8 weeks after start of 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: Point estimate of proportion of patients responding to treatment at 8 weeks is 0.33 (95% CI 0.23-0.45). Tried to enter this result but EudraCT wouldn't accept it as a statistical analysis because it is not comparing two arms, but it is only a one armed trial.
    End point values
    6MP and methotrexate
    Number of subjects analysed
    67
    Units: Patients
    22
    No statistical analyses for this end point

    Secondary: Overall Survival

    Close Top of page
    End point title
    Overall Survival
    End point description
    Overall survival where length of survival is defined in whole days as the time from entry into the study until death from any cause. For those who are not observed to die during the course of the trial will be censored at their last known follow-up date.
    End point type
    Secondary
    End point timeframe
    Over two years of follow-up
    End point values
    6MP and methotrexate
    Number of subjects analysed
    67
    Units: Years
        median (confidence interval 95%)
    10.29 (6.90 to 14.47)
    No statistical analyses for this end point

    Secondary: Progression Free Survival

    Close Top of page
    End point title
    Progression Free Survival
    End point description
    Progression free survival where length of survival is defined in whole days as the time from entry into the study until progression or death from any cause. For those who are not observed to progress or die during the course of the trial will be censored at their last known progression-free follow-up date.
    End point type
    Secondary
    End point timeframe
    Over two years of follow-up.
    End point values
    6MP and methotrexate
    Number of subjects analysed
    67
    Units: Years
        median (confidence interval 95%)
    1.91 (1.71 to 2.24)
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment until end of follow-up.
    Adverse event reporting additional description
    Grade 3 and 4 Adverse events (AE)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    6MP and methotrexate
    Reporting group description
    6MP 55mg/m2 per day, and methotrexate 15mg/m2 per week

    Serious adverse events
    6MP and methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 67 (49.25%)
         number of deaths (all causes)
    52
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Obstruction
    Additional description: Blocked biliary stent
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
    Additional description: TEMPERATURE OF 39.9 DEGREE CELCIUS AND FEELING GENERALLY UNWELL. INFECTIVE PROCESS SUSPECTED, BUT THROAT SWAB, URINE, STOOL SAMPLES, BLOOD CULTURES ALL NEGATIVE. TREATED WITH IV ANTIBIOTICS. SOURCE OF INFECTION NOT IDENTIFIED. HAD NOT BEEN NEUTROPENI
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper Respiratory Infection
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    6MP and methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 67 (68.66%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    19 / 67 (28.36%)
         occurrences all number
    24
    Platelet count decreased
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    White blood cell count decreased
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Hepatobiliary disorders
    Abdominal pain
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    6
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 67 (4.48%)
         occurrences all number
    3

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2011
    Additional trial site and change of PI.
    11 Nov 2011
    Change of PI, plus: To add fallopian tube and primary serous peritoneal cancers to the inclusion criteria. To clarify the assessment of disease progression. To clarify the samples required. To clarify the populations for data analysis. To include all generic forms of the drugs in the protocol.
    21 Aug 2012
    Addition of two new sites.
    12 Oct 2012
    Reduction of starting dose of both IMPs Clarification of definition of objective response Clarification of AE reporting period Addition of study sites
    24 Feb 2014
    To adjust eligibility criteria; the exclusion of patients with low TPMT activity should be removed.

    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 EudraCT system will not allow us to enter the results of all secondary endpoints, i.e. Assessment of feasibility as a multi-centre study. Quality of life, a secondary endpoint, could not be analysed due to the low questionnaire completion rate.
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA