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    Clinical Trial Results:
    A phase I dose escalation safety study combining the ATR inhibitor M6620 with chemoradiotherapy in oesophageal cancer & other sold cancers using time to event continual reassessment method

    Summary
    EudraCT number
    		 2015-003965-27
    Trial protocol
    		 GB  
    Global end of trial date
    04 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2023
    First version publication date
    08 Apr 2023
    Other versions
    Summary report(s)
    		 Stage A1 Full Results
    Stage A2 Full Results

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OCTO-072
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03641547
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Research Governance, Ethics & Assurance, Boundary Brook House, Churchill Drive, Headington , Oxford, United Kingdom, OX3 7GB
    Public contact
    CHARIOT Trial Manager, Oncology Clinical Trials Office, University of Oxford, +44 1865617018, octo-CHARIOT@oncology.ox.ac.uk
    Scientific contact
    CHARIOT Trial Manager, Oncology Clinical Trials Office, University of Oxford, +44 1865617018, octo-CHARIOT@oncology.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
    20 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Stage A1: to find the best tolerated dose of the drug M6620 in combination with palliative radiotherapy in patients with oesophageal cancer. Stage A2: to find the best tolerated dose of the drug M6620 in combination with palliative cisplatin/capecitabine chemotherapy in patients with advanced solid tumours. Stage B: to find the best tolerated M6620 treatment schedule in combination with curative chemoradiotherapy in patients with oesophageal cancer.
    Protection of trial subjects
    The protocol was conducted in compliance with the UK Clinical Trials Regulations, the Principles of Good Clinical Practice (GCP) and the applicable policies of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of investigational medicinal products under the European Union Clinical Trials Directive.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2018
    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: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    0
    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)
    18
    From 65 to 84 years
    17
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Stage A1 (cohort 1): 16 patients were recruited between 17May2019 and 05Jan2022. Stage A2 (cohort 2): 20 patients were recruited between 28Dec2018 and 18Aug2021. Stage B: 0 patients were recruited to this cohort due to lack of funding available.

    Pre-assignment
    Screening details
    		 Stage A1 (cohort 1): 16 patients were recruited between 17May2019 and 05Jan2022. Stage A2 (cohort 2): 20 patients were recruited between 28Dec2018 and 18Aug2021. Stage B: 0 patients were recruited to this cohort due to lack of funding available.

    Period 1
    Period 1 title
    Stage A1 & Stage A2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A2 - Dose level 1
    Arm description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 once a week for 18 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 90 mg/m2 once a week for 18 weeks.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered at 60mg/m2 IV on day 1 of each 21-day cycle for 6 cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered at 625mg/m2 PO BD on days 1-21 of a 21-day cycle for 6 cycles.

    Arm title
    		 A2 - Dose level 2
    Arm description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 twice a week for 18 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 90 mg/m2 twice a week for 18 weeks.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered at 60mg/m2 IV on day 1 of each 21-day cycle for 6 cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered at 625mg/m2 PO BD on days 1-21 of a 21-day cycle for 6 cycles.

    Arm title
    		 A2 - Dose level 3
    Arm description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 once a week for 18 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 140 mg/m2 once a week for 18 weeks.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered at 60mg/m2 IV on day 1 of each 21-day cycle for 6 cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered at 625mg/m2 PO BD on days 1-21 of a 21-day cycle for 6 cycles.

    Arm title
    		 A2 - Dose level 4
    Arm description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 twice a week for 18 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 140 mg/m2 twice a week for 18 weeks.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cisplatin was administered at 60mg/m2 IV on day 1 of each 21-day cycle for 6 cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered at 625mg/m2 PO BD on days 1-21 of a 21-day cycle for 6 cycles.

    Arm title
    		 A1 - Dose level 1
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 9, 16.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 140 mg/m2 on days 2, 9, 16.

    Arm title
    		 A1 - Dose level 2
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 140 mg/m2 on days 2, 5, 9, 12, 16.

    Arm title
    		 A1 - Dose level 3
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16, 19.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 140 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Arm title
    		 A1 - Dose level 4
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 9, 16.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 240 mg/m2 on days 2, 9, 16.

    Arm title
    		 A1 - Dose level 5
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 240 mg/m2 on days 2, 5, 9, 12, 16.

    Arm title
    		 A1 - Dose level 6
    Arm description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16, 19.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M6620 (Berzosertib)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    M6620 (Berzosertib) administered IV at 240 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Number of subjects in period 1
    		A2 - Dose level 1 A2 - Dose level 2 A2 - Dose level 3 A2 - Dose level 4 A1 - Dose level 1 A1 - Dose level 2 A1 - Dose level 3 A1 - Dose level 4 A1 - Dose level 5 A1 - Dose level 6
    Started
    5
    1
    9
    5
    3
    1
    1
    1
    1
    9
    Completed
    2
    1
    4
    3
    3
    1
    1
    1
    1
    9
    Not completed
    3
    0
    5
    2
    0
    0
    0
    0
    0
    0
         Patient decision
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Disease progression
    1
    -
    3
    1
    -
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    2
    -
    -
    -
    -
    -
    -
    -
         Did not start treatment
    1
    -
    -
    1
    -
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A2 - Dose level 1
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 once a week for 18 weeks.

    Reporting group title
    A2 - Dose level 2
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 twice a week for 18 weeks.

    Reporting group title
    A2 - Dose level 3
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 once a week for 18 weeks.

    Reporting group title
    A2 - Dose level 4
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 twice a week for 18 weeks.

    Reporting group title
    A1 - Dose level 1
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 9, 16.

    Reporting group title
    A1 - Dose level 2
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16.

    Reporting group title
    A1 - Dose level 3
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Reporting group title
    A1 - Dose level 4
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 9, 16.

    Reporting group title
    A1 - Dose level 5
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16.

    Reporting group title
    A1 - Dose level 6
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Reporting group values
    		 A2 - Dose level 1 A2 - Dose level 2 A2 - Dose level 3 A2 - Dose level 4 A1 - Dose level 1 A1 - Dose level 2 A1 - Dose level 3 A1 - Dose level 4 A1 - Dose level 5 A1 - Dose level 6 Total
    Number of subjects
    		 5 1 9 5 3 1 1 1 1 9 36
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 3 1 3 3 3 0 1 1 1 2 18
        From 65-84 years
    		 2 0 6 2 0 1 0 0 0 6 17
        85 years and over
    		 0 0 0 0 0 0 0 0 0 1 1
    Gender categorical
    Units: Subjects
        Female
    		 2 0 6 3 0 0 0 1 0 1 13
        Male
    		 3 1 3 2 3 1 1 0 1 8 23
    Ethnicity
    Units: Subjects
        White British
    		 5 1 9 5 3 1 1 1 1 9 36
    Smoking status
    Units: Subjects
        Ex-smoker
    		 1 1 4 3 2 1 1 0 1 6 20
        Never smoked
    		 3 0 5 2 1 0 0 1 0 3 15
        Current smoker
    		 1 0 0 0 0 0 0 0 0 0 1
    Locoregional Disease
    Units: Subjects
        Yes
    		 1 0 6 3 3 1 1 1 1 6 23
        No
    		 4 1 3 2 0 0 0 0 0 3 13
    Distant Metastases
    Units: Subjects
        Yes
    		 5 1 8 5 1 0 0 1 0 4 25
        No
    		 0 0 1 0 2 1 1 0 1 5 11
    Prior Radiotherapy
    Units: Subjects
        Yes
    		 4 1 9 5 0 0 0 0 0 8 27
        No
    		 1 0 0 0 3 1 1 1 1 1 9
    Prior Systemic Treatment
    Units: Subjects
        Yes
    		 4 1 9 5 2 0 1 1 1 8 32
        No
    		 1 0 0 0 1 1 0 0 0 1 4
    Tumour grade
    Units: Subjects
        Well differentiated (G1)
    		 0 0 1 0 1 0 0 0 0 0 2
        Moderately differentiated (G2)
    		 1 1 3 0 1 0 0 0 0 2 8
        Poorly differentiated (G3)
    		 4 0 0 3 0 1 1 1 1 4 15
        Unknown or cannot be assessed (GX)
    		 0 0 5 2 1 0 0 0 0 3 11

    End points

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    End points reporting groups
    Reporting group title
    A2 - Dose level 1
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 once a week for 18 weeks.

    Reporting group title
    A2 - Dose level 2
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 90 mg/m2 twice a week for 18 weeks.

    Reporting group title
    A2 - Dose level 3
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 once a week for 18 weeks.

    Reporting group title
    A2 - Dose level 4
    Reporting group description
    		 Cisplatin/capecitabine + M6620 (Berzosertib) administered at 140 mg/m2 twice a week for 18 weeks.

    Reporting group title
    A1 - Dose level 1
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 9, 16.

    Reporting group title
    A1 - Dose level 2
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16.

    Reporting group title
    A1 - Dose level 3
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 140 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Reporting group title
    A1 - Dose level 4
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 9, 16.

    Reporting group title
    A1 - Dose level 5
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16.

    Reporting group title
    A1 - Dose level 6
    Reporting group description
    		 Radiotherapy + M6620 (Berzosertib) administered at 240 mg/m2 on days 2, 5, 9, 12, 16, 19.

    Primary: To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose (RPTD)) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageal cancer

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    End point title
    		 To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose (RPTD)) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageal cancer [1]
    End point description
    Highest treatment schedule resulting in less than 25% dose limiting toxicity (DLT) rate
    End point type
    Primary
    End point timeframe
    9 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 2 different stages in the baseline period - Stage A1 and Stage A2. The Stages in are independent of each other and so analyses relating to the two sets of arms are reported separately.
    End point values
    		 A1 - Dose level 1 A1 - Dose level 2 A1 - Dose level 3 A1 - Dose level 4 A1 - Dose level 5 A1 - Dose level 6
    Number of subjects analysed
    3
    1
    1
    1
    1
    9
    Units: Dose Limiting Toxicities
    0
    0
    0
    0
    0
    0
    Attachments
    		 A1 DLTs
    A1 Primary Results
    Statistical analysis title
    		 TiTE-CRM
    Statistical analysis description
    The primary analysis is performed using the Time-To-Event Continual Reassessment Method (TiTE-CRM). Giving posterior estimates for the probability of toxicity (DLT) at each dose level
    Comparison groups
    A1 - Dose level 1 v A1 - Dose level 2 v A1 - Dose level 3 v A1 - Dose level 4 v A1 - Dose level 5 v A1 - Dose level 6
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Post prob of tox at dose level 6
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.165
    Notes
    [2] - Bayesian TiTE-CRM

    Primary: To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose (RPTD)) administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer

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    End point title
    		 To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose (RPTD)) administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer [3]
    End point description
    Highest treatment schedule resulting in less than 30% dose limiting toxicity (DLT) rate
    End point type
    Primary
    End point timeframe
    4 Weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There are 2 different stages in the baseline period - Stage A1 and Stage A2. The Stages in are independent of each other and so analyses relating to the two sets of arms are reported separately.
    End point values
    		 A2 - Dose level 1 A2 - Dose level 2 A2 - Dose level 3 A2 - Dose level 4
    Number of subjects analysed
    4
    1
    9
    4
    Units: Dose Limiting Toxicities
    0
    0
    2
    0
    Attachments
    		 A2 DLTs
    A2 Primary Results
    Statistical analysis title
    		 TiTE-CRM (A2)
    Statistical analysis description
    The primary analysis is performed using the Time-To-Event Continual Reassessment Method (TiTECRM). Giving posterior estimates for the probability of toxicity (DLT) at each dose level
    Comparison groups
    A2 - Dose level 1 v A2 - Dose level 2 v A2 - Dose level 3 v A2 - Dose level 4
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Post prob of tox at dose level 4
    Point estimate
    0.185
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.397
    Notes
    [4] - Bayesian TiTE-CRM

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Stage A1 (cohort 1): adverse events were reported from first dose of IMP to patients' 12-week follow up visit. Stage A2 (cohort 2): adverse events were reported from first dose of IMP to follow up visit at 8 weeks post-end of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Stage A1 (cohort 1)
    Reporting group description
    		 Patients administered M6620 (Berzosertib) in combination with palliative radiotherapy in oesophageal cancer.

    Reporting group title
    Stage A2 (cohort 2)
    Reporting group description
    		 Patients administered M6620 (Berzosertib) in combination with cisplatin/capecitabine chemotherapy in metastatic or advanced inoperable solid tumours.

    Serious adverse events
    		 Stage A1 (cohort 1) Stage A2 (cohort 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 18 (16.67%)
         number of deaths (all causes)
    9
    11
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Gastrostomy tube site complication
    Additional description: Rig accidentally fallen out
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Stage A1 (cohort 1) Stage A2 (cohort 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    18 / 18 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign; malignant and unspecified
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 18 (22.22%)
         occurrences all number
    1
    5
    General disorders and administration site conditions
    General Disorders & Administration Site Conditions
         subjects affected / exposed
    7 / 16 (43.75%)
    13 / 18 (72.22%)
         occurrences all number
    10
    43
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    8 / 16 (50.00%)
    8 / 18 (44.44%)
         occurrences all number
    11
    14
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Investigations
         subjects affected / exposed
    4 / 16 (25.00%)
    8 / 18 (44.44%)
         occurrences all number
    7
    25
    Injury, poisoning and procedural complications
    Injury; poisoning and procedural complications
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 18 (5.56%)
         occurrences all number
    2
    2
    Nervous system disorders
    Nervous System Disorders
         subjects affected / exposed
    4 / 16 (25.00%)
    5 / 18 (27.78%)
         occurrences all number
    6
    6
    Blood and lymphatic system disorders
    Blood & Lymphatic System Disorders
         subjects affected / exposed
    3 / 16 (18.75%)
    12 / 18 (66.67%)
         occurrences all number
    5
    37
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    0
    6
    Eye disorders
    Eye disorders
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Gastrointestinal Disorders
         subjects affected / exposed
    13 / 16 (81.25%)
    12 / 18 (66.67%)
         occurrences all number
    28
    39
    Hepatobiliary disorders
    Hepatobiliary
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    6 / 16 (37.50%)
    4 / 18 (22.22%)
         occurrences all number
    14
    12
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal & Connective Tissue Disorders
         subjects affected / exposed
    3 / 16 (18.75%)
    7 / 18 (38.89%)
         occurrences all number
    4
    12
    Infections and infestations
    Infections & Infestations
         subjects affected / exposed
    3 / 16 (18.75%)
    10 / 18 (55.56%)
         occurrences all number
    3
    20
    Metabolism and nutrition disorders
    Metabolism & Nutrition Disorders
         subjects affected / exposed
    5 / 16 (31.25%)
    10 / 18 (55.56%)
         occurrences all number
    6
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2017
    Amendment_001: Substantial amendment following review of protocol by MHRA and Chemotherapy Pharmacy Advisory Service (CPAS) during initial submission process and prior to obtaining approvals to proceed.
    15 May 2018
    Amendment_002: Substantial amendment following change of IMP name from VX-970 to M6620 and manufacturer from Vertex Pharmaceutical Inc. to Merck KGaA. Included, *Additional secondary endpoint to Stage A2 (in-field radiotherapy control) *Change in PI at two recruiting NHS sites and additional NHS recruiting site *Update to definition of end of study *Clarification of DLT definition wording *Update to ionising radiation exposure assessment due to one site having a higher standard of care dose than initially planned for *Minor clarifications/corrections to trial documents.
    08 Aug 2018
    Amendment_003: Substantial amendment following changes to IMP supply chain (manufacturing and assembly sites, drug distribution and transport, QC/QP release).
    27 Oct 2020
    Amendment_004: Substantial amendment to change design of Stage B. Including, *Fewer treatment levels *Confirmation of dosage based on data from Stages A1 and A2 *Reduced follow up period *IB update and Reference Safety Information *Update to DLT definitions *Clarification of treatment for patients experiencing DLT *Clarification on data used in treatment allocation decisions *Increased flexibility in gaps between participant treatment start dates (Stage A1 & A2) *Removal of Carboplatin for Cisplatin toxicity *Removal of PK sampling endpoint (Stage A2) *Changes to eligibility criteria to allow patients with larger tumours to participate *Collection of Stage A1 archival biopsy samples *Reduction in requirement to monitor for reactions after M6620 administration if prior administrations have shown no reaction *Haemoglobin values requirements for M6620 administration corrected *Correction of RTTQA oversight details *Change in PI at an NHS recruiting site *Patient cards updated with out of hours guidance *Minor clarifications/corrections to trial documents.
    03 Aug 2021
    Amendment_005: Change of PI at NHS recruiting site.

    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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