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    Clinical Trial Results:
    Phase II, randomised, placebo controlled, multicentre, feasibility study of low dose (metronomic) cyclophosphamide with or without nintedanib (BIBF 1120) in advanced ovarian cancer (METRO-BIBF)

    Summary
    EudraCT number
    2011-005814-12
    Trial protocol
    GB  
    Global end of trial date
    11 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jan 2019
    First version publication date
    23 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL10/0470
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01610869
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Trial Co-ordinator, CR UK and UCL Cancer Trials Centre, +44 02076799237, ctc.metrobibf@ucl.ac.uk
    Scientific contact
    Trial Co-ordinator, CR UK and UCL Cancer Trials Centre, +44 02076799237, ctc.metrobibf@ucl.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
    07 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The trial objectives are to explore the efficacy and safety of an all oral combination of nintedanib (an inhibitor of angiogenic signalling) and metronomic cyclophosphamide in patients with multiply-relapsed advanced ovarian cancer, who have completed a minimum of two lines of previous chemotherapy and who for any reason are not suitable for further ‘standard’ intravenous chemotherapy treatments.
    Protection of trial subjects
    The first 12 patients randomised were reviewed for toxicity every three weeks for the first 12 weeks, the data was reviewed by the Independent Data Monitoring Committee (IDMC) and the dosage was considered acceptable and patients were assessed 6 weekly thereafter. The IDMC further reviewed toxicity data and serious adverse events (SAEs) in July 2015, and this resulted in a decision to reduce the starting dose of nintedanib/matching placebo to 150mg b.d.. Patients randomised at this starting dose were reviewed at 3 and 6 weeks and thereafter every 6 weeks. Patients received oral nintedanib and cyclophosphamide or cyclophosphamide and matched placebo continuously until disease progression, death or unacceptable toxicity. Patient safety was monitored using regular patient assessments, dose modification guidance, regular review of safety data by the IDMC and Trial Management Group (TMG) and through strict eligibility criteria. Patient data was stored in a secure manner and UCL CTC trials are registered in accordance with the Data Protection Act 1998 and the Data Protection Officer at UCL.
    Background therapy
    Patients were given a supply of a suitable antiemetic as per local guidelines, to take as required for any nausea experienced with cyclophosphamide. Some patients required steroids as per local guidelines, for symptom control and this was permitted as was any other medication such as analgesia or laxatives for palliation of symptoms. All concomitant medication was recorded.
    Evidence for comparator
    Cyclophosphamide has been used in the treatment of malignancies including breast and ovarian cancer for decades. All patients in the trial received cyclophosphamide +/- nintedanib. In ovarian cancer, angiogenesis has been shown to have a central role in both disease progression and prognosis. A direct relationship has been demonstrated between the expression of biomarkers for angiogenesis such as VEGF, the degree of neovascularization and the behaviour of epithelial ovarian cancers. These data suggest that pharmacological inhibitors of angiogenesis may have the capacity to arrest tumour progression. Several phase II trials of different antiangiogenic drugs have demonstrated activity against relapsed ovarian cancer. Nintedanib is a potent, orally available triple kinase inhibitor targeting VEGFRs, PDGFRs, and FGFRs. The specific and simultaneous abrogation of these pathways results in effective growth inhibition of both endothelial and, via PDGF- and FGF-receptors of perivascular cells, which may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. Furthermore, signalling by FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the VEGF pathway is disrupted. In addition preclinical models show that nintedanib may have a direct anti-tumour effect on those malignant cells which overexpress PDGFR and/or FGFR. Previous studies have shown that nintedanib is generally well tolerated with mild to moderate adverse effects such as gastrointestinal symptoms (nausea, diarrhoea, vomiting, abdominal pain) and reversible elevations of liver enzymes. A randomised phase II maintenance trial in ovarian cancer in which the efficacy and safety of nine months of continuous twice daily doses of nintedanib following chemotherapy was investigated, has identified the potential activity of nintedanib with a 36-week progression free survival (PFS) of 14.3 % compared to 5.0 % in the control group.
    Actual start date of recruitment
    26 Aug 2014
    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: 117
    Worldwide total number of subjects
    117
    EEA total number of subjects
    117
    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)
    62
    From 65 to 84 years
    55
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    117 patients were randomised from NHS hospitals across the UK between 26/08/2014 and 26/10/2016. 3 patients did not start the investigational drug and are excluded from this EudraCT submission. The planned recruitment end date was 01/10/2017 (with 124 patients), but recruitment was suspended early following IDMC review due to lack of efficacy.

    Pre-assignment
    Screening details
    - Medical History (must have had >2 lines chemotherapy for ovarian cancer) - Clinical examination - blood pressure, ECG, ECOG - CT/MRI scan - Liver function tests: AST and/or ALT, alkaline phosphatase, bilirubin and albumin - Haematology, coagulation parameters and biochemistry - Tumour marker (CA125) - Urinalysis for proteinuria

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Carer, Assessor, Subject
    Blinding implementation details
    Use of a matched placebo. The IWRS/IVRS system was used for randomised allocation, trial medication assignment, initial drug supply of nintedanib/placebo and resupply, discontinuation from study treatment, emergency code breaks (i.e. unblinding) and trial drug shipment confirmation. The IWRS/IVRS technology was managed and maintained by Almac Clinical Technologies. The system was accessible via the internet 24 hours a day, 7 days a week.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Control Arm
    Arm description
    Placebo and cyclophosphamide
    Arm type
    Placebo

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg tablets b.d. - daily dose of 100mg. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    At randomisation the dose administered will be 150-200 mg twice daily of placebo (depending on the date the patient was randomised). Placebo will be provided in 150 mg and 100 mg capsules so, depending on date of randomisation, patients will either take two 100 mg capsules in the morning and another two capsules approximately 12 hours later OR one x 150mg capsule in the morning and another one approximately 12 hours later. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.

    Arm title
    Investigation arm
    Arm description
    Nintedanib and cyclophosphamide
    Arm type
    Experimental

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg tablets b.d. - daily dose of 100mg. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    At randomisation the dose administered will be 150-200 mg twice daily of nintedanib (depending on the date the patient was randomised). Nintedanib will be provided in 150 mg and 100 mg capsules so, depending on date of randomisation, patients will either take two 100 mg capsules in the morning and another two capsules approximately 12 hours later OR one x 150mg capsule in the morning and another one approximately 12 hours later. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.

    Number of subjects in period 1 [1]
    Control Arm Investigation arm
    Started
    55
    59
    Completed
    55
    59
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: As 3 patients did not start the study treatment, they have been excluded from the analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control Arm
    Reporting group description
    Placebo and cyclophosphamide

    Reporting group title
    Investigation arm
    Reporting group description
    Nintedanib and cyclophosphamide

    Reporting group values
    Control Arm Investigation arm Total
    Number of subjects
    55 59 114
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    65.7 (56.4 to 69.8) 62.4 (54.7 to 70.2) -
    Gender categorical
    Units: Subjects
        Female
    55 59 114
        Male
    0 0 0
    Subject analysis sets

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    These are the 114 patients who started the study drug

    Subject analysis sets values
    Safety analysis
    Number of subjects
    114
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    63.9 (55.4 to 69.9)
    Gender categorical
    Units: Subjects
        Female
    114
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Control Arm
    Reporting group description
    Placebo and cyclophosphamide

    Reporting group title
    Investigation arm
    Reporting group description
    Nintedanib and cyclophosphamide

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    These are the 114 patients who started the study drug

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Primary
    End point timeframe
    Over the follow-up period
    End point values
    Control Arm Investigation arm Safety analysis
    Number of subjects analysed
    55
    59
    114
    Units: number of patients
    55
    59
    114
    Statistical analysis title
    Overall survival analysis
    Comparison groups
    Investigation arm v Control Arm v Safety analysis
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.81
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.57

    Secondary: Progression free survival

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    End point title
    Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    over the follow-up period
    End point values
    Control Arm Investigation arm Safety analysis
    Number of subjects analysed
    55
    59
    114
    Units: number of patients
    55
    59
    114
    Statistical analysis title
    Progression-free survival analysis
    Comparison groups
    Control Arm v Investigation arm v Safety analysis
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.61
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.32

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From informed consent to 30 days post last trial treatment administration.
    Adverse event reporting additional description
    Clinical assessment and self-reported patient diary.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Full reporting of adverse events will be done via the publication in a scientific journal

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2013
    Filter Q2e amended in REC Application Form Change of PI at Mount Vernon Hospital
    11 Dec 2013
    Change of PI at St James’s University Hospital and Royal United Hospital
    07 Apr 2014
    Updated protocol v2.0, updated IB for nintedanib, updated SmPC for cyclophosphamide, pregnancy monitoring PIS and CF: - Update to trial management group members - Updates to summary of trial design - Details of circulating tumour cell sub-study added (sponsored by East and North Herts NHS Trust). MRI sub-study removed - Information on incidence of ovarian cancer updated - PT removed as a coagulation parameter - Total (rather than indirect) and Direct Bilirubin required if bilirubin elevated - Total protein and calcium tests removed from screening assessments - Albumin added as a screening assessment - Clarification regarding treatment breaks added - Clarification that patient must be 18 years or older to be eligible - Clarification LMWH and warfarin treatment allowed (i.e. not an exclusion criteria), reference to in dwelling venous catheter removed. - Clarification regarding INR ranges in the presence/absence of therapeutic anticoagulants- - PT removed as a coagulation parameter. - Amended- patients on therapeutic anticoagulants with APTT greater than 2.5xULN not eligible (previously 1.5xULN). - Added extra information - poorly controlled diabetes mellitus or patient on sulphonylurea-type hypoglycaemics (e.g. glicazide) as main diabetic control (as contraindicated with cyclophosphamide) - Clarified VEGF within 4 weeks of study treatment (rather than study start) - Stratification factor – number of previous lines of chemotherapy corrected to ≤3 or >3 - Placebo added as IMP - Clarification that patients can have a maximum of three treatment breaks of less than 21 days, if more they need to contact the UCL CTC to discuss continued treatment - Clarification that re-screening must be performed for patients who have discontinued previous study treatment due to DLT or other adverse events for 21 to 30 days
    07 Nov 2014
    Change of PI at St James’s University
    14 Jul 2015
    Urgent Safety Measure: trial recruitment halted following IDMC review requiring revision to protocol start dose for nintedanib
    10 Sep 2015
    Updated protocol v3 following urgent safety measure: - Update to trial management group members - Trial schema updated in line with new nintedanib start dose (150mg b.d.) and new week 3 safety visit - Introduction updated with information from IB version 14 (19Jan2015); the outcome of the July 2015 IDMC review; results from trials that have reported since last protocol update. - Clarification that there are no data available for patients with an inherited pre-disposition to bleeding or for patients receiving a full dose of anticoagulant treatment prior to starting treatment with nintedanib, therefore careful monitoring and caution is advised in this group of patients - Secondary end point added to confirm response according to RECIST 1.1 and GCIG will be assessed where data available (as mentioned in inclusion criteria) - Baseline MRI scan included as pre-randomisation evaluation if patient known to have stable brain metastases - Urinalysis for proteinuria included in screening investigation table - Clarification re-screening procedure in section 8.2 also needs to be followed if patient does not start treatment within 14 days of randomisation - Updated in line with new nintedanib start dose (150mg b.d.) and new week 3 safety visit for all patients randomised after July 2015 - Clarification on eligibility criteria and randomisation procedure - Further guidance added regarding dose modifications - Nintedanib with dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations - Clarification to the emergency unblinding procedure - 3 weekly assessment table removed as safety cohort closed and trial patients no longer on 3 weekly visits - (6 weekly assessments) updated to include week 3 safety visit, check for germline BRCA mutation status (where information available) at baseline
    27 Oct 2015
    Updated investigator's brochure from Boehringer Ingelheim Ltd.
    23 Sep 2016
    Updated investigator's brochure from Boehringer Ingelheim Ltd.
    08 Nov 2016
    Recruitment suspension following IDMC recommendation.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Jul 2015
    Following an IDMC review in July 2015 of adverse event data in this Phase II trial, a significant imbalance in the incidence of high grade (grade 3 and above) adverse events between the two arms of the study was noted, leading to the conclusion that there is a high probability that the combination of nintedanib and metronomic cyclophosphamide at the prescribed doses is not well tolerated in this population of patients. These events are spread over a number of different organ systems and are on the whole expected events for nintedanib and/or a consequence of having advanced and multiply relapsed ovarian cancer. Although these events occur at various time-points, a significant proportion occur within the first 6 weeks of treatment. Therefore, an Urgent Safety Measure (USM) was implemented on 14/07/2015 closing the trial to recruitment temporarily. The protocol amendment that was in the process of being drafted prior to the USM was updated to include safety measures to improve the tolerability of the regimen for patients already on the trial and for those to be recruited in future: the start dose of nintedanib was reduced to 150mg BD for new patients with mandatory 3 week visits for the first 6 weeks scheduled to enable general toxicity/symptom control review including repeat blood tests. However, it was noted that some patients did tolerate the higher 200mg dose nintedanib/placebo without any such adverse events and it was agreed patients who were still receiving 200mg BD nintedanib/placebo at the time of this review may continue on this dose at the discretion of the treating investigators. The trial reopened to recruitment in November 2015, after the protocol amendment (v3.0) was approved by by the competent authorities on 15/09/2015 (REC) and 19/10/2015 (MHRA). The first site was reopened to recruitment on 12/11/2015; all remaining sites were reactivated to recruitment by August 2016.
    12 Nov 2015
    26 Oct 2016
    The IDMC reviewed the safety and efficacy of the trial in October 2016 following the previously reported Urgent Safety Measure which prompted a temporary recruitment suspension and protocol amendment to reduce the starting dose of nintedanib (200 mg BD to 150mg BD) and add a week 3 visit for all new patients randomised to the trial. The IDMC concluded that the safety profile was acceptable following the dose reduction in the nintedanib group, however the lack of superior efficacy in the combined regime resulted in an early suspension of recruitment on 26/10/2016. The total number of patients recruited to the trial is 117, slightly short of the 124 target. The TSC, IDMC and TMG agreed that patients who were still taking trial drug could continue trial treatment if the patient and clinician felt that this was appropriate. They considered there was no change in the overall safety assessment of the oral combination of nintedanib and cyclophosphamide.
    -

    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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