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    Clinical Trial Results:
    A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

    Summary
    EudraCT number
    2015-003639-37
    Trial protocol
    GB  
    Global end of trial date
    09 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2019
    First version publication date
    30 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4198C00003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02583477
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    35 Gatehouse Drive, Waltham, Massachusetts, United States, 02451
    Public contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@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
    09 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Cohort 1: To assess the safety and tolerability of MEDI4736 in combination with nab-paclitaxel + gemcitabine. Cohort 2: To assess the safety, tolerability and objective response rate (ORR) for MEDI4736 + AZD5069 in combination.
    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 Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    27
    EEA total number of subjects
    24
    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)
    20
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study consisted of 2 independent cohorts, each of which ran at separate times between 25 March 2016 and 09 July 2018. In Cohort 1, participants were recruited from 1 center in the United States; in Cohort 2, participants were recruited from 6 centers in the United Kingdom.

    Pre-assignment
    Screening details
    Participants underwent screening evaluations to determine eligibility within 4 weeks (28 days) prior to first administration of the Investigational Product (IP). A total of 27 participants (3 participants in Cohort 1 and 24 participants in Cohort 2) were enrolled into the study, of which 23 participants received treatment.

    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
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
    Arm description
    Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Durvalumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 1.5 g IV infusion on Day 1 of each 28-day cycle.

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel 125 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine 1000 mg/m^2 IV infusion over 30 minutes immediately after the completion of nab-paclitaxel administration on Days 1, 8, and 15 of each 28-day cycle.

    Arm title
    Cohort 2 (MEDI4736 + AZD5069)
    Arm description
    Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
    Arm type
    Experimental

    Investigational medicinal product name
    AZD5069
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A starting dose of 80 mg orally bid (with dose reductions to 40 mg bid or 20 mg bid for toxicity allowable) in the morning and evening. AZD5069 was provided as 40 mg and 10 mg tablets.

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Durvalumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 1.5 g IV infusion on Day 1 of each 28-day cycle.

    Number of subjects in period 1
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069)
    Started
    3
    24
    Received treatment
    3
    20
    Completed treatment
    0
    0
    Completed
    0
    0
    Not completed
    3
    24
         Study terminated
    2
    2
         Death
    1
    16
         Did not receive treatment
    -
    4
         Adverse event, non-fatal
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
    Reporting group description
    Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 2 (MEDI4736 + AZD5069)
    Reporting group description
    Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group values
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069) Total
    Number of subjects
    3 24 27
    Age, Customized
    Units: Subjects
        <50 years
    0 4 4
        >=50 - <65 years
    1 15 16
        >=65 - <75 years
    2 5 7
    Sex: Female, Male
    Units: Subjects
        Female
    2 10 12
        Male
    1 14 15
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    0 2 2
        White
    3 21 24
        Other
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
    Reporting group description
    Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 2 (MEDI4736 + AZD5069)
    Reporting group description
    Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Primary: Number of Participants With Dose-Limiting Toxicities (DLT)

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    End point title
    Number of Participants With Dose-Limiting Toxicities (DLT) [1]
    End point description
    DLT period was defined as first treatment cycle for Cohort 1, and first dose of AZD5069 and MEDI4736 to end of Cycle 1 or until a participant experienced a DLT, whichever occurs first for Cohort 2. A DLT was any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 during DLT period. •Liver transaminase elevation >= 5× but <= 8× upper limit of normal (ULN) that doesn’t resolve to Grade 2 within 5 days •Transaminase elevation > 8× ULN or total bilirubin > 5× ULN •Any Grade 4 immune-related AE (irAE) not attributed to local tumor response, Grade >=3 colitis, Grade >=2 pneumonitis that doesn’t resolve to <= Grade 1 within 7 days, Grade 3 irAE, that doesn’t resolve to Grade <=1 or baseline status within 14 days •Any Grade >=3 non-irAE toxicity that doesn’t resolve to Grade <=1 or baseline status within 14 days. A DLT was any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period. The DLT evaluable set analysed.
    End point type
    Primary
    End point timeframe
    Cohort 1: From time of first dose of MEDI4736 on Day 1 up to Day 28 of Cycle 1 and Cohort 2: From time of first dose of AZD5069 and MEDI4736 on Day 1 up to Day 28 of Cycle 1 or until a participant experiences a DLT, whichever occurs first.
    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: Descriptive statistical analysis was performed for the outcome measure.
    End point values
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    3
    12
    Units: participants
    0
    4
    No statistical analyses for this end point

    Primary: Number of Participants With AEs

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    End point title
    Number of Participants With AEs [2]
    End point description
    An AE is development of an undesirable medical condition or deterioration of a pre-existing medical condition following or during exposure to study treatment, whether or not considered causally related to study treatment. An undesirable medical condition can be symptoms, signs or abnormal results of an investigation. A serious AE (SAE) is an AE that fulfills one or more following criteria: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital abnormality or birth defect, and an important medical event that may jeopardize participant or may require medical intervention to prevent one of outcomes listed above. AEs leading discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs presented. The safety analysis set analysed.
    End point type
    Primary
    End point timeframe
    From first dose of study treatment administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis was performed for the outcome measure.
    End point values
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    3
    20
    Units: participants
        Any AE
    3
    20
        Any AE causally related to treatment (CRT)
    3
    14
        Any AE of CTCAE Grade 3 or higher
    3
    18
        Any AE of CTCAE Grade 3 or higher CRT
    3
    10
        Any AE leading discontinuation of study treatment
    2
    3
        Any AE with outcome of death
    1
    4
        Any AE with outcome of death CRT
    1
    0
        Any SAE
    1
    16
        Any SAE CRT
    1
    8
    No statistical analyses for this end point

    Primary: Objective Response Rate in Cohort 2

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    End point title
    Objective Response Rate in Cohort 2 [3] [4]
    End point description
    ORR is defined as the percentage of participants with a confirmed overall response of complete response (CR) or partial response (PR). A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 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. CR is defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD were not met. ORR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). The efficacy analysis set analysed.
    End point type
    Primary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
    Notes
    [3] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    [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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 80%)
    5.6 (0.58 to 19.95)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) in Cohort 2

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    End point title
    Duration of Response (DoR) in Cohort 2 [5]
    End point description
    DoR was defined as the time from the first documentation of CR/PR (which is subsequently confirmed) until the date of progression/death, or the last evaluable RECIST assessment for participants that did not progress or did progress after 2 missed visits of the last evaluable assessment (or first dose). PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. DoR was determined using Investigator assessments according to RECIST v1.1 and was calculated using the Kaplan-Meier technique. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
    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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    1
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    18.29 (18.29 to 18.29)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) in Cohort 2

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    End point title
    Disease Control Rate (DCR) in Cohort 2 [6]
    End point description
    DCR at 6 months is defined as the percentage of participants who had a best objective response (BoR) of CR or PR in the first 6 months (i.e. 24+1=25 weeks to allow for a late assessment within the assessment window) or who had demonstrated stable disease (SD) for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. DCR at 12 months is defined as the percentage of participants who had a BoR of CR or PR in the first 12 months (i.e. 48+1=49 weeks to allow for a late assessment within the assessment window) or who had demonstrated SD for a minimum interval of 48 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 329 days) following the start of treatment. DCR was determined using Investigator assessments according to RECIST v1.1. The efficacy analysis set analysed.
    End point type
    Secondary
    End point timeframe
    RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days for first 48 weeks up to 6 months and 12 months
    Notes
    [6] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
    number (not applicable)
        At 6 months
    11.1
        At 12 months
    5.6
    No statistical analyses for this end point

    Secondary: Median Progression-Free Survival (PFS) in Cohort 2

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    End point title
    Median Progression-Free Survival (PFS) in Cohort 2 [7]
    End point description
    PFS is defined as the time from the date of first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from allocated therapy or receives another anticancer therapy prior to progression. PFS was determined using Investigator assessments according to RECIST v1.1 and calculated using the Kaplan-Meier technique. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
    Notes
    [7] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: months
        number (not applicable)
    1.6
    No statistical analyses for this end point

    Secondary: Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2

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    End point title
    Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2 [8]
    End point description
    The PFS6 was defined as percentage of participants alive and progression-free after 6 months. The PFS6 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months
    Notes
    [8] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 80%)
    11.1 (3.91 to 22.55)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2

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    End point title
    Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2 [9]
    End point description
    The PFS rate was defined as percentage of participants alive and progression-free after 3 months. The PFS3 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months
    Notes
    [9] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 80%)
    11.1 (3.91 to 22.55)
    No statistical analyses for this end point

    Secondary: Median Overall Survival (OS) in Cohort 2

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    End point title
    Median Overall Survival (OS) in Cohort 2 [10]
    End point description
    OS is defined as the time from the date of first dose until death due to any cause (i.e. date of death or censoring – date of first dose + 1). OS was calculated using the Kaplan-Meier technique. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (censored at end of study). The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
    Notes
    [10] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: months
        number (not applicable)
    2.8
    No statistical analyses for this end point

    Secondary: Overall Survival at 6 Months (OS6) in Cohort 2

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    End point title
    Overall Survival at 6 Months (OS6) in Cohort 2 [11]
    End point description
    OS6 is defined as percentage of participants alive at 6 months from first dose of study treatment. OS6 was calculated using the Kaplan-Meier estimate of OS at 6 months. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to 6 months
    Notes
    [11] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 80%)
    22.2 (11.19 to 35.59)
    No statistical analyses for this end point

    Secondary: Overall Survival at 12 Months (OS12) in Cohort 2

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    End point title
    Overall Survival at 12 Months (OS12) in Cohort 2 [12]
    End point description
    OS12 is defined as percentage of participants alive at 12 months from first dose of study treatment. OS12 was calculated using the Kaplan-Meier estimate of OS at 12 months. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment (Day 1) up to 12 months
    Notes
    [12] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 80%)
    14.8 (5.74 to 27.92)
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2

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    End point title
    Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2 [13]
    End point description
    Samples were measured for the presence of ADAs and ADA-neutralizing antibodies for MEDI4736 using validated assays. Persistently positive is defined as positive at >=2 post-baseline assessments or positive at the last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available. NAB = neutralizing antibody.
    End point type
    Secondary
    End point timeframe
    On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose
    Notes
    [13] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    20
    Units: participants
        Positive at any visit
    3
        Both baseline and post-baseline positive
    0
        Only post-baseline positive
    1
        Only baseline positive
    2
        ADA persistently positive
    0
        ADA transiently positive
    1
        ADA positive participants who are NAB positive
    0
    No statistical analyses for this end point

    Secondary: Mean Plasma Concentrations of MEDI4736 in Cohort 2

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    End point title
    Mean Plasma Concentrations of MEDI4736 in Cohort 2 [14]
    End point description
    Mean peak and trough plasma concentrations of MEDI4736 are presented. The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses. 99999 denotes "standard deviation cannot be calculated when only one participant analyzed". Here, 'n' is number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and post infusion (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1 and 7
    Notes
    [14] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    20
    Units: nanograms per milliliter
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: Predose (n=2)
    1444.730 ± 1010.7667
        Cycle 1 Day 1: Post infusion (n=20)
    339342.229 ± 95923.6405
        Cycle 2 Day 1: Predose (n=11)
    56773.555 ± 17716.8788
        Cycle 3 Day 1: Predose (n=6)
    63655.840 ± 26425.8402
        Cycle 4 Day 1: Predose (n=4)
    69325.233 ± 22750.3387
        Cycle 7 Day 1: Predose (n=1)
    79687.820 ± 99999
        Cycle 7 Day 1: Post infusion (n=1)
    435297.610 ± 99999
    No statistical analyses for this end point

    Secondary: Mean Plasma Concentrations of AZD5069 in Cohort 2

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    End point title
    Mean Plasma Concentrations of AZD5069 in Cohort 2 [15]
    End point description
    Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile. The PK analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses. 99999 denotes "standard deviation cannot be calculated when only one participant analyzed". Here, 'n' is number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and postdose (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1, 2, and 7
    Notes
    [15] - 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: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only.
    End point values
    Cohort 2 (MEDI4736 + AZD5069)
    Number of subjects analysed
    20
    Units: nanomoles per liter
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: Predose (n=20)
    10.60 ± 42.933
        Cycle 1 Day 1: Postdose (n=19)
    2236.29 ± 1678.496
        Cycle 2 Day 1: Predose (n=11)
    1829.36 ± 1473.533
        Cycle 2 Day 1: Postdose (n=1)
    24.40 ± 99999
        Cycle 3 Day 1: Predose (n=5)
    502.48 ± 601.914
        Cycle 4 Day 1: Predose (n=4)
    1345.00 ± 1068.666
        Cycle 7 Day 1: Predose (n=1)
    1200.00 ± 99999
        Cycle 7 Day 1: Postdose (n=1)
    7540.00 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From initial IP administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
    Adverse event reporting additional description
    The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
    Reporting group description
    Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Reporting group title
    Cohort 2 (MEDI4736 + AZD5069)
    Reporting group description
    Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.

    Serious adverse events
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    17 / 20 (85.00%)
         number of deaths (all causes)
    1
    16
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Obstruction gastric
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypovolaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Biliary sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) Cohort 2 (MEDI4736 + AZD5069)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    20 / 20 (100.00%)
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Tumour associated fever
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Administration site mass
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    10 / 20 (50.00%)
         occurrences all number
    2
    11
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Skin wound
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Soft tissue injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Blood creatinine increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    4
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Citrobacter test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    4
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Neutropenia
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 20 (10.00%)
         occurrences all number
    6
    2
    Leukopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 20 (10.00%)
         occurrences all number
    1
    3
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 20 (30.00%)
         occurrences all number
    0
    7
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Aptyalism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 20 (20.00%)
         occurrences all number
    2
    7
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    0
    6
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Colitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Glossodynia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    9 / 20 (45.00%)
         occurrences all number
    1
    11
    Melaena
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Parotid gland enlargement
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Rectal discharge
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Steatorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    0
    5
    Peptic ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tongue coated
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    9 / 20 (45.00%)
         occurrences all number
    1
    12
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Polyuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Alopecia
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Vasculitic rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Skin mass
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 20 (35.00%)
         occurrences all number
    2
    8
    Diabetes mellitus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    5
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    Iron deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 20 (25.00%)
         occurrences all number
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2016
    Updated dose rationale and treatment regimens regarding dose of AZD5069 used, inclusion criteria #3 and #9, and exclusion criteria #14, #15, and #20. Replacement criteria for withdrawn participants in Cohort 1/2 and definition of “evaluable patient” for Cohort 2 clarified. Use, type, and period of contraception before, during, and after trial clarified. Footnotes b, d, and j of Tables 2 and 3 were updated. Removal of section regarding tumor assessment in participants who omit Day 15 dose administration. Removal of requirement for central reading of scans. Management of participants was based solely upon results of assessment conducted by Investigator. Electrocardiogram (ECG) frequency for Cohort 2 updated to screening and Day 1 of each cycle. Vital signs collection time points predose, during and post-dose in Section 5.2.4 clarified. Sections 5.4.5, 5.4.7, and 5.5.5 regarding Biobank used in study amended. Updated to state that recording of AEs in also refers to AESIs. Addition of AESIs associated with MEDI4736. Removal of dose reduction or modification guidance of AZD5069 in as this document does not exist. MEDI4736 dosage and strength clarified. Table 9 removed from Section 7.1.1. Removal of omission of Day 15 treatment in case of participant toxicity Figure 3 updated to correct week schedule of MEDI4736 dose 7. Added clarification that use of cannabinoids must be avoided in participants administered with AZD5069 alone and in combination with MEDI4736. Removal of overall survival text from, as it is duplicate of paragraph. Corrected errors in disease control rate and progression free survival calculation. Start date of study clarified. Removal of soluble programmed cell death ligand 1 tests throughout Protocol. Removal of “lesions <2 centimeters biopsied within screening period (fresh tumor biopsy)” as a non-measurable lesion in as it does not pertain to imaging/RECIST 1.1. Updated toxicity management guidelines to current version.
    14 Dec 2016
    Language was updated to reflect fact that recruitment to Cohort 1 was stopped after only 3 participants had been enrolled. Efficacy, immunogenicity and exploratory objectives were removed. New exploratory objectives added. Sections of AZD5069 dose rationale were updated to include language on how dosing was to be managed in Cohort 2, including details regarding a dosing regimen being established at time in Study D4660C00004. Updated introduction, inclusion criterion #3, and exclusion criterion #11, #14, #16, and #19. Discontinuation criterion #9 updated to remove “and Investigator determination that participants is no longer benefiting from treatment with IP”. Updated to remove PK, immunogenicity, and biomarker collections from Cohort 1; included collection of circulating soluble factors, pharmacogenetic sample, circulating tumor DNA and updated times for myeloid-derived suppressor cells and peripheral blood mononuclear cells. Updated to specify that 12-lead ECGs were to be recorded in triplicate for Cohort 2. Updated to reflect which samples were to be analyzed for each cohort. Pharmacogenetics section added for Cohort 2. Added toxicity management for AZD5069 40 mg starting dose. Removed all DLT evaluation text for Cohort 1 and included DLT information for Cohort 2. Updated probability table data for Tables 10 and 11. Added table of posterior probabilities of true DLT incidence >33% with various priors as well as explanatory text for Table 12. Disease control rate was to be evaluated at 6 and 12 months, instead of 3 months. Updated to include most current version of “MEDI4736 Dosing Modification and Toxicity Management Guidelines”. Added information regarding dose toxicity management and alternative dosing regimen for AZD5069 80 mg twice daily currently under exploration.
    17 Jul 2017
    Language was updated to reflect the initial dosing of AZD5069 at 80 mg orally twice daily, with provision for dose reductions described in Section 6.7.3. Text throughout Protocol has been updated for consistency. Primary objective was clarified to be inclusive of safety and tolerability of MEDI4736 + AZD5069 in combination, thus separate safety objective was removed. Section has been updated to include the most current clinical data available for MEDI4736. Inclusion criterion #3 text was simplified and Cohort 2 progression timeline for prior therapy was removed. Added inclusion criterion #9 (Cohort 2) for taking mandatory tumor biopsy in screening period (or <45 days prior to first dosing if adequate tissue samples are available). Text throughout the Protocol has been updated for consistency.
    08 Feb 2018
    Blood sample changed to ‘serum or plasma’ and non-compartmental analysis removed. Potential risks of MEDI4736 updated to reflect MEDI4736 Investigator’s Brochure Edition 12. Neutropenia/neutrophil count decreased was considered expected for regulatory purposes in the respiratory indication only, but not yet in the oncology population (change arising from alignment with the clinical trials facilitation group Guidelines). Additional sensitivity analysis for overall response rate was removed.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to a programmatic decision, enrollment of additional participants to cohort 1 was not pursued. Study terminated by sponsor.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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