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    Clinical Trial Results:
    A Phase II, Open-Label, Multi-Arm Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients with Platinum Refractory Extensive-Stage Small-Cell Lung Cancer (BALTIC)

    Summary
    EudraCT number
    2016-001202-42
    Trial protocol
    HU   DE   ES   PL  
    Global end of trial date
    27 Nov 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Jun 2024
    First version publication date
    08 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D419QC00002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02937818
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    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
    18 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the preliminary efficacy of each treatment arm in terms of objective response rate.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonization/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics. The Principal Investigator ensured that each patient was given full and adequate oral and written information about the study. Patients provided signed and dated informed consent before any procedure specific to the study was conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Nov 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Ukraine: 20
    Worldwide total number of subjects
    72
    EEA total number of subjects
    52
    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)
    47
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 11 study centers in 5 countries (Germany, Hungary, Poland, Spain, and Ukraine).

    Pre-assignment
    Screening details
    Subjects who met the inclusion exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.

    Period 1
    Period 1 title
    Overall Study (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
    Arm A: Durvalumab + Tremelimumab (Original Cohort)
    Arm description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed progressive disease (PD), or other discontinuation criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 75 mg tremelimumab every 4 weeks.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 1500 mg durvalumab every 4 weeks.

    Arm title
    Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Arm description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed PD, or other discontinuation criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 75 mg tremelimumab every 4 weeks.

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 1500 mg durvalumab every 4 weeks.

    Arm title
    Arm B: Adavosertib + Carboplatin
    Arm description
    Subjects orally received adavosertib 225 mg twice daily (BID) for 2.5 days from Day 1 + carboplatin area under the curve (AUC) 5 Day 1 IV, every 3 weeks (q3w).
    Arm type
    Experimental

    Investigational medicinal product name
    Adavosertib
    Investigational medicinal product code
    AZD1775
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 225 mg adavosertib twice daily.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carboplatin, at a dose calculated to produce an area under the curve (AUC) of 5 every 3 weeks.

    Arm title
    Arm C: Ceralasertib (AZD6738) + Olaparib
    Arm description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.
    Arm type
    Experimental

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 300 mg olaparib twice daily.

    Investigational medicinal product name
    Ceralasertib
    Investigational medicinal product code
    AZD6738
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 160 mg ceralasertib once daily.

    Number of subjects in period 1
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Started
    21
    20
    10
    21
    Completed
    0
    0
    0
    0
    Not completed
    21
    20
    10
    21
         Subjects decision
    1
    -
    1
    1
         Disease progression
    17
    14
    7
    18
         Subjects ongoing durvalumab at Data cut off (DCO)
    1
    2
    -
    -
         Adverse event, non-fatal
    2
    4
    1
    1
         Subjects ongoing ceralasertib and olaparib at DCO
    -
    -
    -
    1
         Condition under investigation worsened
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Original Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed progressive disease (PD), or other discontinuation criteria.

    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed PD, or other discontinuation criteria.

    Reporting group title
    Arm B: Adavosertib + Carboplatin
    Reporting group description
    Subjects orally received adavosertib 225 mg twice daily (BID) for 2.5 days from Day 1 + carboplatin area under the curve (AUC) 5 Day 1 IV, every 3 weeks (q3w).

    Reporting group title
    Arm C: Ceralasertib (AZD6738) + Olaparib
    Reporting group description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Reporting group values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib Total
    Number of subjects
    21 20 10 21 72
    Age Categorical
    Units: Subjects
        < 50
    2 0 1 2 5
        ≥ 50 to < 65
    13 12 5 12 42
        ≥ 65 to < 75
    6 6 3 5 20
        ≥ 75 to < 80
    0 2 1 2 5
        ≥ 80
    0 0 0 0 0
    Sex: Female, Male
    Units: Subjects
        Female
    6 4 2 7 19
        Male
    15 16 8 14 53
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 0 0 0 0
        White
    21 20 10 21 72
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 1 0 0 1
        Not Hispanic or Latino
    21 19 10 21 71
        Unknown or Not Reported
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Original Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed progressive disease (PD), or other discontinuation criteria.

    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed PD, or other discontinuation criteria.

    Reporting group title
    Arm B: Adavosertib + Carboplatin
    Reporting group description
    Subjects orally received adavosertib 225 mg twice daily (BID) for 2.5 days from Day 1 + carboplatin area under the curve (AUC) 5 Day 1 IV, every 3 weeks (q3w).

    Reporting group title
    Arm C: Ceralasertib (AZD6738) + Olaparib
    Reporting group description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Ceralasertib (AZD6738)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Olaparib
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Ceralasertib (AZD6738)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Ceralasertib (AZD6738)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Olaparib
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Subject analysis set title
    Olaparib
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Primary: Number of Subjects With Overall Response

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    End point title
    Number of Subjects With Overall Response [1]
    End point description
    Overall Response Rate (ORR) using Investigator assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. ORR was defined as the number (percentage) of subjects with a confirmed Complete Response (CR) or confirmed Partial Response (PR) and was estimated for each treatment arm with corresponding 2-sided 95% exact confidence intervals (CIs). A confirmed response of CR/PR meant that a response of CR/PR was recorded at one visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit, and not less than 4 weeks after the visit when the response was first observed, with no evidence of progression between the initial and CR/PR confirmation visit.
    End point type
    Primary
    End point timeframe
    Until disease progression [PD] (Up to 3.5 Years)
    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: Pharmacokinetics parameters were not calculated for Arm A: Durvalumab + Tremelimumab.
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    21
    20
    10
    21
    Units: Subjects
    2
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    Duration of Response (DoR)
    End point description
    The DoR was defined as the time from the date of first documented response (which was subsequently confirmed) CR/PR until the date of documented progression, or death in the absence of disease progression. The DoR in subjects with confirmed objective response are reported. Here, arbitrary number 999.999 denotes data not available as objective response not reached.
    End point type
    Secondary
    End point timeframe
    Until disease progression or data cut-off (DCO) or Death (Up to 3.5 Years)
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    2
    1
    0 [2]
    1
    Units: Months
        median (full range (min-max))
    999.999 (1.5 to 999.999)
    3 (3 to 3)
    ( to )
    8.5 (8.5 to 8.5)
    Notes
    [2] - All subjects were classified as non-responders
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Control at 12 Weeks

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    End point title
    Percentage of Subjects With Disease Control at 12 Weeks
    End point description
    The disease control rate (DCR) at 12 weeks was defined as the percentage of subjects who had a best objective response of CR or PR in the first 13 weeks or who had demonstrated stable disease (SD) for a minimum interval of 11 weeks following the start of study treatment. The DCR was determined programmatically based on RECIST 1.1 using site Investigator data and all data up until the first progression event.
    End point type
    Secondary
    End point timeframe
    At 12 Weeks
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    21
    20
    10
    21
    Units: Percentage of subjects
        number (not applicable)
    38.1
    15.0
    30.0
    38.1
    No statistical analyses for this end point

    Secondary: Time to Response (TTR)

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    End point title
    Time to Response (TTR)
    End point description
    The TTR (per RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first dose until the first date of documented response.
    End point type
    Secondary
    End point timeframe
    Until disease progression or DCO or Death (Up to 3.5 Years)
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    2
    1
    0 [3]
    1
    Units: Months
        median (full range (min-max))
    1.8 (1.7 to 1.8)
    1.8 (1.8 to 1.8)
    ( to )
    1.7 (1.7 to 1.7)
    Notes
    [3] - There were no responses.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    The PFS (per RECIST 1.1 according to the Investigator’s assessment) was defined as the time from the date of the first dose of study treatment until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdrew from allocated therapy or received another anti-cancer therapy prior to progression.
    End point type
    Secondary
    End point timeframe
    Until disease progression or DCO or Death (Up to 3.5 Years)
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    21
    20
    10
    21
    Units: Months
        median (confidence interval 95%)
    1.91 (1.77 to 4.34)
    1.77 (1.02 to 2.20)
    2.60 (0.56 to 4.83)
    2.92 (1.81 to 4.53)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    The OS was defined as the time from the date of the first dose of study treatment until death due to any cause.
    End point type
    Secondary
    End point timeframe
    Until disease progression or DCO or Death (Up to 3.5 Years)
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    21
    20
    10
    21
    Units: Months
        median (confidence interval 95%)
    5.95 (1.91 to 10.61)
    3.37 (1.91 to 7.66)
    4.67 (0.56 to 5.98)
    7.56 (4.21 to 12.58)
    No statistical analyses for this end point

    Secondary: Time to maximum concentration (tmax)

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    End point title
    Time to maximum concentration (tmax)
    End point description
    Time to maximum concentration for ceralasertib and olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    21
    21
    Units: Hour
        median (full range (min-max))
    1.250 (1.00 to 6.08)
    1.800 (1.00 to 6.08)
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax)

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    End point title
    Maximum concentration (Cmax)
    End point description
    Maximum concentration for ceralasertib and olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    21
    21
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    4.215 ± 27.7129
    6.558 ± 39.9411
    No statistical analyses for this end point

    Secondary: Partial area under the concentration-time curve (AUC0-6)

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    End point title
    Partial area under the concentration-time curve (AUC0-6)
    End point description
    Partial area under the concentration-time curve for ceralasertib and olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
    End point values
    Olaparib Ceralasertib (AZD6738)
    Number of subjects analysed
    21
    20
    Units: h*µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1
    26.356 ± 42.2963
    18.346 ± 34.6952
        Cycle 1, Day 7
    42.016 ± 33.7599
    23.666 ± 23.9202
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t)

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    End point title
    Area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t)
    End point description
    Area under the concentration-time curve from time zero to the last measurable concentration for Ceralasertib and Olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 1 (post-dose) and Cycle 1 Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    21
    21
    Units: h*µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 1
    18.575 ± 34.5074
    26.973 ± 41.4461
        Cycle 1, Day 7
    24.061 ± 23.0923
    62.535 ± 42.4552
    No statistical analyses for this end point

    Secondary: Time to maximum concentration at steady state (tmax,ss)

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    End point title
    Time to maximum concentration at steady state (tmax,ss)
    End point description
    Time to maximum concentration at steady state for Ceralasertib and Olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    10
    10
    Units: Hour
        median (full range (min-max))
    1.875 (0.63 to 6.08)
    2.708 (0.63 to 4.50)
    No statistical analyses for this end point

    Secondary: Maximum concentration at steady state (Cmax,ss)

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    End point title
    Maximum concentration at steady state (Cmax,ss)
    End point description
    Maximum concentration at steady state for Ceralasertib and Olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    10
    10
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    5.176 ± 23.4058
    9.189 ± 30.4888
    No statistical analyses for this end point

    Secondary: Minimum concentration at steady state (Cmin,ss)

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    End point title
    Minimum concentration at steady state (Cmin,ss)
    End point description
    Minimum concentration at steady state for Ceralasertib and Olaparib are reported.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    10
    10
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    1.119 ± 55.9070
    2.376 ± 61.8191
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve at steady state (AUCss)

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    End point title
    Area under the concentration-time curve at steady state (AUCss)
    End point description
    Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported. Here, arbitary number 999.999 denotes data not available as there were not enough pharmacokinetic data points collected to calculate AUCss.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    10
    9
    Units: h*µg/mL
        geometric mean (geometric coefficient of variation)
    999.999 ± 999.999
    67.929 ± 37.4297
    No statistical analyses for this end point

    Secondary: Apparent clearance of drug at steady state at steady state (CLss/F)

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    End point title
    Apparent clearance of drug at steady state at steady state (CLss/F)
    End point description
    Area under the concentration-time curve at steady state at steady state for Ceralasertib and Olaparib are reported. Here, arbitary number 999.999 denotes data not available as there were not enough pharmacokinetic data points collected to calculate CLss/F.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (each cycle was 28 days in length) Day 7 (pre-dose and post-dose)
    End point values
    Ceralasertib (AZD6738) Olaparib
    Number of subjects analysed
    10
    9
    Units: Litre/hour
        geometric mean (geometric coefficient of variation)
    999.999 ± 999.999
    4.416 ± 42.3171
    No statistical analyses for this end point

    Secondary: Serum concentrations of Durvalumab and Tremelimumab

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    End point title
    Serum concentrations of Durvalumab and Tremelimumab [4]
    End point description
    Serum concentrations of Durvalumab and Tremelimumab are reported.
    End point type
    Secondary
    End point timeframe
    Durvalumab: Cycle 1 (each cycle was 4 weeks) Day 1(post-dose); Cycle 2 Day 1(pre-dose); Cycle 5 Day 1 (pre-dose); Tremelimumab: Cycle 1 (each cycle was 4 weeks) Day 1 (post-dose); Cycle 2 Day 1 (predose); Cycle 5 Day 1 (No dose); Cycle 7 Day 1 (No dose)
    Notes
    [4] - 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: Pharmacokinetics parameters were not calculated for Arm A: Durvalumab + Tremelimumab.
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort)
    Number of subjects analysed
    21
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Durvalumab: Cycle 1 Day 1 (Post-dose)
    391.192 ± 23.5990
        Durvalumab: Cycle 2 Day 1 (Pre-dose)
    55.590 ± 53.0745
        Durvalumab: Cycle 5 Day 1 (Pre-dose)
    116.846 ± 51.0036
        Tremelimumab: Cycle 1 Day 1 (Post-dose)
    18.299 ± 20.8181
        Tremelimumab: Cycle 2 Day 1 (Pre-dose)
    2.650 ± 53.1007
        Tremelimumab: Cycle 5 Day 1 (No dose)
    5.005 ± 38.3784
        Tremelimumab: Cycle 7 Day 1 (No dose)
    0.784 ± 66.3469
    No statistical analyses for this end point

    Secondary: Plasma concentrations of Adavosertib and Carboplatin

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    End point title
    Plasma concentrations of Adavosertib and Carboplatin [5]
    End point description
    Plasma concentrations of Adavosertib and Carboplatin are reported.
    End point type
    Secondary
    End point timeframe
    Adavosertib: Cycle 1 (each cycle was 21 days) Day 3 (pre-dose and post-dose); Cycle 3 Day 3 (pre-dose and post-dose); Carboplatin: Cycle 1 (each cycle was 21 days) Day 1 (post-dose)
    Notes
    [5] - 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: Pharmacokinetics parameters were not calculated for Arm A: Durvalumab + Tremelimumab.
    End point values
    Arm B: Adavosertib + Carboplatin
    Number of subjects analysed
    10
    Units: nM
    geometric mean (geometric coefficient of variation)
        Adavosertib: Cycle 1 Day 3 (Pre-dose)
    551.489 ± 41.5823
        Adavosertib: Cycle 1 Day 3 (Post-dose)
    728.342 ± 62.3968
        Adavosertib: Cycle 3 Day 3 (Pre-dose)
    606.571 ± 46.7716
        Adavosertib: Cycle 3 Day 3 (Post-dose)
    805.270 ± 68.0275
        Carboplatin: Cycle 1 Day 1 (Post-dose)
    12834.615 ± 27.5493
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event.
    End point type
    Secondary
    End point timeframe
    Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
    End point values
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm A: Durvalumab + Tremelimumab (Expansion Cohort) Arm B: Adavosertib + Carboplatin Arm C: Ceralasertib (AZD6738) + Olaparib
    Number of subjects analysed
    21
    20
    10
    21
    Units: Subjects
        Any AE
    16
    17
    8
    18
        Any AE causally related to any study treatment
    10
    9
    8
    16
        Any AE with outcome = death
    1
    0
    1
    1
        Any SAE
    6
    8
    4
    7
        Any AE to discontinuation of any study treatment
    2
    4
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 until disease progression, and follow-up visit (Up to 3.5 Years)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Original Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed progressive disease (PD), or other discontinuation criteria.

    Reporting group title
    Arm C: Ceralasertib (AZD6738) + Olaparib
    Reporting group description
    Subjects orally received ceralasertib 160 mg once daily (QD) Days 1 to 7 + olaparib 300 mg BID Days 1 to 28, q4w.

    Reporting group title
    Arm B: Adavosertib + Carboplatin
    Reporting group description
    Subjects orally received adavosertib 225 mg twice daily (BID) for 2.5 days from Day 1 + carboplatin area under the curve (AUC) 5 Day 1 IV, every 3 weeks (q3w).

    Reporting group title
    Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Reporting group description
    Subjects received durvalumab 1500 mg + tremelimumab 75 mg via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy 1500 mg via IV infusion q4w, starting on Week 16 until confirmed PD, or other discontinuation criteria.

    Serious adverse events
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm C: Ceralasertib (AZD6738) + Olaparib Arm B: Adavosertib + Carboplatin Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    7 / 21 (33.33%)
    4 / 10 (40.00%)
    8 / 20 (40.00%)
         number of deaths (all causes)
    19
    15
    10
    16
         number of deaths resulting from adverse events
    1
    1
    1
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns third degree
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Myasthenic syndrome
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 21 (19.05%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A: Durvalumab + Tremelimumab (Original Cohort) Arm C: Ceralasertib (AZD6738) + Olaparib Arm B: Adavosertib + Carboplatin Arm A: Durvalumab + Tremelimumab (Expansion Cohort)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 21 (76.19%)
    18 / 21 (85.71%)
    8 / 10 (80.00%)
    17 / 20 (85.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 21 (23.81%)
    1 / 21 (4.76%)
    3 / 10 (30.00%)
    1 / 20 (5.00%)
         occurrences all number
    6
    1
    6
    1
    Asthenia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    3 / 10 (30.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    1
    6
    2
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    1
    1
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    3
    1
    0
    4
    Dyspnoea
         subjects affected / exposed
    6 / 21 (28.57%)
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    1
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dry throat
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    0
    1
    0
    4
    Anxiety
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    Rib fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    2 / 10 (20.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    2
    1
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Somnolence
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    11 / 21 (52.38%)
    3 / 10 (30.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    11
    5
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    7 / 10 (70.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    13
    1
    Neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    3 / 10 (30.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    13
    2
    Leukopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    6 / 10 (60.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    4
    13
    3
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 21 (14.29%)
    3 / 10 (30.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    4
    6
    2
    Diarrhoea
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
    7 / 10 (70.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    1
    14
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin induration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    0
    2
    Hypothyroidism
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    1
    0
    0
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 21 (9.52%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    0
    2
    Arthralgia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    0
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Bronchitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 21 (4.76%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Influenza
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 21 (4.76%)
    2 / 10 (20.00%)
    3 / 20 (15.00%)
         occurrences all number
    1
    1
    3
    3
    Hyperchloraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2017
    Amendment 1 (Version 2): Addition of the timelines between progression and enrolment to target population in Synopsis. -Changes related to weigh based dosing for patients whose weight falls to 30kg or in Changes related to weigh based dosing for patients whose weight falls to 30kg. -Clarification added to inclusion criteria 3, and 4 regarding stage at initial diagnosis and timelines between progression and enrollment respectively, and exclusion criteria 10, and Section 8.7.1 regarding use of sensitive substrates of CYP3A4. -Information added to Study plan and timing of procedures regarding relevant assessments.-Change related to the time of validity of laboratory samples between screening and baseline was from 7 days to 3 days. -clarification added to Section 7.6 Overdose. -Additional information added on Rationale for four cycles of combination therapy followed by durvalumab monotherapy. -Removal of Section 12.7.1.2 Tremelimumab as there will be no tremelimumab monotherapy in the trial. -Information added to Sections 2.7.2, 2.7.2.1, 2.7.2.2 and 2.7.2.3 regarding identified and potential risks for durvalumab, tremelimumab and durvalumab + tremelimumab. -Information added to Section 5 regarding reasons for potential dosing delay. -Additional information added to Section 4.5 regarding AZD1775 dosing. -Addition of a section regarding Patients with a history of Torsades de pointes to the Restrictions Section 4.5.2. -Clarification added to section 7.3.3.3 Nausea and vomiting regarding aprepitant [Emend] and fosaprepitant. - Clarification added to Appendix B Figure 2 AZD1775 + carboplatin therapy dosing schedule. -Addition of Section 8.7.3 Substances known to prolong the ECG QTc interval.
    15 Dec 2017
    Amendment 2 (Version 3): Treatment Arm C added to protocol – subprotocol for this Arm is included in APPENDIX C. -Clarification to interim analysis description was added in Synopsis section to clarify the action taken in event of a decision to close Arm after stage 1. -Exploratory objective and specification for Arms was added to Section 3.4, Study Objectives. -Clarification added to Section 4.9 on discontinuation of investigational product. - Information added in Section 4.10.2 regarding possible replacement of withdrawn subjects. -Clarification was added in Section 4.10.3 on consent withdrawal. -Time period for collection of adverse events, revised to address events post the defined safety follow-up period. -Information added to Appendix A, Section 2.8 to provide clarity on study design for Arm A. -Clarification added to inclusion criterion 5 in Appendix A, section 4.1 on prohibition of use of granulocyte-colony stimulating factor for neutrophils raising during screening. -Updated Appendix A Table 7 Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 Monotherapy or Combination therapy with Tremelimumab or Tremelimumab Monotherapy) to version from 1 Nov 2017. -Information was added to Appendix B Section 7.2.2 regarding paternal exposure.
    25 Jun 2018
    Amendment 3 (Version 4): Protocol synopsis and Section 2.2.1 Rationale for study design were updated to allow expansion of any arm, to a total of 40 eligible subjects, based on Review Committee assessment of data from the first 20 subjects. -Exploratory objectives were updated for clarification and to allow analysis of further biomarkers including circulating tumour DNA (ctDNA) and tumour mutation burden (TMB). -Synopsis Statistical Methods section and Section 9.2 Sample Size Estimate of Master protocol updated to correct typos, include a row in the table for 40 subjects and remove the column for 25%. -Benefit-risk updated with 6 and 12 months OS data. -Methods for assigning treatment groups updated to clarify that parallel recruitment is allowed. -Information added to Section 6.1 to clarify how to follow up if subjects discontinue study treatment prior to PD. -Analysis following expansion added to explain there is no need for further interim analysis in that group of patients and describe planned sensitivity analysis. -Rationale for study design, doses, and control groups updated to include scientific rationale for expanding Arm A. -Durvalumab and tremelimumab dose and treatment regimen justification updated with latest data and durvalumab IB. -Schedule of assessments updated to remove biomarker samples that are not collected (e.g. CTCs), added (e.g. ctDNA) and tighten requirements for tumour biopsy material. Footnotes updated to clarify that some samples are not required in the expansion group (including PK, anti-drug antibodies (ADA) and mRNA). -Schedule of assessments (post-discontinuation) updated regarding PK samples to clarify not required for expansion group. -Updated to reflect the wording on optional exploratory genetic sample informed consent form, consistent with current durvalumab template. -Updated to reflect information included in latest olaparib IB (edition 15). -
    16 Jan 2020
    Amendment 4 (Version 5): Sections on durvalumab and tremelimumab monotherapies and combined therapy updated as per current IBs in Appendix A. - Dosing Modification and Toxicity Management Guidelines for durvalumab and tremelimumab separated from Appendix A (i.e. Arm A study protocol). -Removal of the requirement to collect PK samples after Cycle 6 in Arm C. -Haematological parameters for ongoing treatment, and guidance for dose modifications revised as per updated Cerelasertib guidance.

    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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