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    Clinical Trial Results:
    A Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Subjects With Previously Untreated, Advanced Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    2010-023854-35
    Trial protocol
    DE   HU   BG  
    Global end of trial date
    04 Sep 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Dec 2020
    First version publication date
    23 Jun 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CD-ON-MEDI-575-1031
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01268059
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, 20878
    Public contact
    Mohammed Dar, MD, Vice President & Head, Clinical Development, Oncology, MedImmune, LLC, +1 301-398-0000, information.center@astrazeneca.com
    Scientific contact
    Mohammed Dar, MD, Vice President & Head, Clinical Development, Oncology, MedImmune, LLC, +1 301-398-0000, 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
    04 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    For phase 1b, main objective was evaluation of the safety profile of MEDI-575 when used in combination with carboplatin/paclitaxel in participants with previously untreated, advanced non-small cell lung cancer (NSCLC). For phase 2, main objective was evaluation of progression-free survival of subjects following treatment with MEDI-575 when used in combination with paclitaxel/carboplatin versus paclitaxel/carboplatin alone in participants with previously untreated, advanced NSCLC.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating participant signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 64
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Japan: 14
    Worldwide total number of subjects
    99
    EEA total number of subjects
    9
    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)
    50
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Overall, 99 participants were enrolled in study, (4 participants, all from North America sites, were enrolled in Phase 1b and 95 participants in Phase 2 of study). Of 95 participants, 14 were from Japan, 81 were from North American and European Union (EU) sites. End of study is 14 months from last participant enrolled, or sponsor stopped study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Carboplatin/Paclitaxel (C/P): North America/EU Population
    Arm description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 6 milligram per milliliter into minute [mg/mL*min] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 milligram per square meter [mg/m^2] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Arm title
    C/P + MEDI-575 (C/P/M): North America/EU Population
    Arm description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI-575
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) once every 21 days on Day 1 for a total of 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 6 milligram per milliliter into minute [mg/mL*min] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 milligram per square meter [mg/m^2] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Arm title
    Carboplatin/Paclitaxel (C/P): Japan Population
    Arm description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) administered as an IV infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 6 milligram per milliliter into minute [mg/mL*min] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 milligram per square meter [mg/m^2] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Arm title
    C/P + MEDI-575 (C/P/M): Japan Population
    Arm description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.
    Arm type
    Experimental

    Investigational medicinal product name
    MEDI-575
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) once every 21 days on Day 1 for a total of 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin 6 milligram per milliliter into minute [mg/mL*min] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 milligram per square meter [mg/m^2] once every 21 days on Day 1, for a total of 6 doses (cycles).

    Number of subjects in period 1
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Started
    40
    45
    6
    8
    Completed
    12
    10
    3
    3
    Not completed
    28
    35
    3
    5
         Death
    20
    30
    3
    5
         Progression of disease
    1
    -
    -
    -
         Consent withdrawn by subject
    7
    4
    -
    -
         Lost to follow-up
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carboplatin/Paclitaxel (C/P): North America/EU Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Reporting group title
    C/P + MEDI-575 (C/P/M): North America/EU Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Reporting group title
    Carboplatin/Paclitaxel (C/P): Japan Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) administered as an IV infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Reporting group title
    C/P + MEDI-575 (C/P/M): Japan Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Reporting group values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population Total
    Number of subjects
    40 45 6 8 99
    Age categorical
    Units: Subjects
        less than or equal to (<=) 70 years
    35 32 6 6 79
        greater than (>) 70 years
    5 13 0 2 20
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.0 ± 6.6 65.1 ± 8.2 57.5 ± 13.9 65.9 ± 6.0 -
    Gender, Male/Female
    Units: participants
        Female
    17 17 2 2 38
        Male
    23 28 4 6 61
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    0 1 6 8 15
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    3 5 0 0 8
        White
    37 39 0 0 76
        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
    1 2 0 0 3
        Not Hispanic or Latino
    39 43 6 8 96
        Unknown or Not Reported
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Carboplatin/Paclitaxel (C/P): North America/EU Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Reporting group title
    C/P + MEDI-575 (C/P/M): North America/EU Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Reporting group title
    Carboplatin/Paclitaxel (C/P): Japan Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) administered as an IV infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Reporting group title
    C/P + MEDI-575 (C/P/M): Japan Population
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Subject analysis set title
    Carboplatin/Paclitaxel (Total)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Subject analysis set title
    Carboplatin/Paclitaxel + MEDI-575 (Total)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Subject analysis set title
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Subject analysis set title
    Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Subject analysis set title
    Carboplatin/Paclitaxel - Phase 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Primary: Number of Participants With Dose Limiting Toxicities (DLT): Phase 1b

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    End point title
    Number of Participants With Dose Limiting Toxicities (DLT): Phase 1b [1]
    End point description
    A DLT was defined as: 1. Any treatment-related Grade 3 or higher non-hematologic toxicity that occurred during the DLT assessment period with the following exceptions: a. Grade 3 fever (in the absence of neutropenia) defined as more than (>) 40.0 degree Celcius (> 104.0 degree Fahrenheit) that resolved to normal or baseline within 24 hours of treatment and was not considered a serious adverse event (SAE); or b. Grade 3 rigors/chills that responded to optimal therapy. 2. Any treatment-related Grade 3 or higher hematologic toxicity. The evaluable population for dose determination included all participants who were in Phase 1b, received at least 1 full cycle of MEDI-575 and completed the safety follow-up through the DLT evaluation period or participants who experienced any DLT.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 21 of first cycle
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point. As listed in the table, there were 4 subjects dosed and analyzed and 0 experienced a DLT.
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b
    Number of subjects analysed
    4
    Units: participants
    0
    No statistical analyses for this end point

    Primary: Progression Free-Survival (PFS)

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    End point title
    Progression Free-Survival (PFS) [2]
    End point description
    Progression-free survival defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (defined according to Response Evaluation Criteria for Solid Tumors [RECIST] guidelines) or death due to any cause, whichever occurs first. Participants without progression or death at the time of analysis were censored at their last date of tumor evaluation. PFS was assessed only in North America/European Union (EU) participants. The Intent-to-Treat (ITT) North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study.
    End point type
    Primary
    End point timeframe
    From randomization until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    Notes
    [2] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population
    Number of subjects analysed
    19
    27
    Units: months
        median (confidence interval 95%)
    5.5 (4.7 to 6.5)
    4.6 (3.9 to 5.5)
    Statistical analysis title
    PFS
    Statistical analysis description
    Progression-free Survival (ITT Phase 2 North America/EU Population) for Carboplatin/Paclitaxel + MEDI-575 versus Carboplatin/Paclitaxel
    Comparison groups
    Carboplatin/Paclitaxel (C/P): North America/EU Population v C/P + MEDI-575 (C/P/M): North America/EU Population
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.027 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.205
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    4.5
    Notes
    [3] - Hazard ratio and its 95 percent (%) confidence interval ( CIs) were calculated using the Cox proportional hazard model stratified by histology, disease stage, and Eastern Cooperative Oncology Group (ECOG) performance status.
    [4] - The 2-sided p-value was calculated using the log-rank test stratified by histology, disease stage, and ECOG performance status.

    Secondary: Best Overall Response

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    End point title
    Best Overall Response
    End point description
    Best overall response of a participant was defined as the best tumor response [Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)] observed during the trial period assessed according to the RECIST version 1.1 criteria. The participant’s best overall response assignment depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30 percent (%) in the sum of diameters of target lesion, SD was defined as steady state of disease, and PD was defined as an increase of at least 20% in the sum of diameters of target lesions. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    40
    41
    6
    8
    Units: participants
        Complete response
    1
    0
    0
    0
        Partial response
    12
    19
    2
    1
        Stable disease
    19
    12
    3
    5
        Progressive disease
    1
    5
    1
    1
        Unknown
    7
    5
    0
    1
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    The ORR defined as the percentage of participants with confirmed CR or confirmed PR according to RECIST guidelines. Confirmed responses were those that persist on repeat imaging or assessment greater than or equal to (>=) 4 weeks after the initial documentation of response. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    40
    41
    6
    8
    Units: percentage of participants
        number (confidence interval 95%)
    22.5 (10.8 to 38.5)
    31.7 (18.1 to 48.1)
    33.3 (4.3 to 77.7)
    12.5 (0.3 to 52.7)
    Statistical analysis title
    ORR (North America/EU)
    Statistical analysis description
    Objective Response Rate Comparision for Carboplatin/Paclitaxel + MEDI-575 versus Carboplatin/Paclitaxel.
    Comparison groups
    Carboplatin/Paclitaxel (C/P): North America/EU Population v C/P + MEDI-575 (C/P/M): North America/EU Population
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.487 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - The 2-sided p-value was calculated by adjusting for the stratification factors histology, disease stage, and Eastern Cooperative Oncology Group (ECOG) performance status.
    Statistical analysis title
    ORR (Japan)
    Statistical analysis description
    Treatment effect Carboplatin/Paclitaxel + MEDI-575 versus Carboplatin/Paclitaxel.
    Comparison groups
    Carboplatin/Paclitaxel (C/P): Japan Population v C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.386 [6]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - The 2-sided p-value was calculated by adjusting for the stratification factors histology, disease stage, and ECOG performance status.

    Secondary: Time to Response (TTR)

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    End point title
    Time to Response (TTR)
    End point description
    TTR was measured from randomization to the first documentation of objective response and assessed only in participants who achieved objective response. The ORR defined as the percentage of participants with confirmed CR or confirmed PR according to RECIST guidelines. Confirmed responses were those that persist on repeat imaging or assessment >=4 weeks after the initial documentation of response. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study. Participants who achieved OR were analyzed for this outcome measure. In the below table 0.9999 and 99999 indicates that the 95% confidence interval was not estimated because only 1 participant had OR in the specified arm.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    9
    13
    2
    1
    Units: months
        median (confidence interval 95%)
    1.4 (1.2 to 2.7)
    1.4 (1.3 to 1.6)
    2.2 (1.4 to 3.1)
    2.8 (0.9999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    Duration of Response (DR)
    End point description
    The DR defined as the duration from the first documentation of objective response to the first documented disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study. Participants who achieved OR were analyzed for this outcome measure. In the below table 0.9999 and 99999 indicates the 95% confidence interval was not estimated because only 1 participants had OR in the specified arm.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    9
    13
    2
    1
    Units: months
        median (confidence interval 95%)
    3.3 (1.3 to 4.6)
    4.2 (3.7 to 5.0)
    4.9 (3.5 to 6.3)
    2.1 (0.9999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    The TTP was measured from randomization until the documentation of disease progression. Disease progression defined according to RECIST v 1.1 guidelines. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study. The TTP was analyzed for only those participants who had disease progression.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    13
    23
    5
    6
    Units: months
        number (confidence interval 95%)
    6.4 (4.9 to 10.3)
    4.6 (3.9 to 6.4)
    6.5 (1.4 to 10.7)
    4.6 (1.3 to 15.0)
    Statistical analysis title
    TTP (North America/EU)
    Comparison groups
    Carboplatin/Paclitaxel (C/P): North America/EU Population v C/P + MEDI-575 (C/P/M): North America/EU Population
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    3.017
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    7.4
    Statistical analysis title
    TTP (Japan)
    Comparison groups
    Carboplatin/Paclitaxel (C/P): Japan Population v C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.134
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    4.3

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival defined as the time from randomization until death due to any cause. Participants who were still alive at the time of analysis were censored at their last date of last contact. In the below table 99999 indicates that median and confidence interval were not determined as an insufficient number of participants had the event. The ITT North America/EU population included all North America/EU participants who were randomized into Phase 2 portion of the study. The ITT Japanese population included all Japanese participants who were randomized into the Phase 2 portion of the study.
    End point type
    Secondary
    End point timeframe
    From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (C/P): North America/EU Population C/P + MEDI-575 (C/P/M): North America/EU Population Carboplatin/Paclitaxel (C/P): Japan Population C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects analysed
    20
    27
    3
    5
    Units: months
        number (confidence interval 95%)
    11.8 (8.2 to 99999)
    10.0 (6.4 to 11.6)
    99999 (4.3 to 99999)
    11.5 (2.3 to 99999)
    Statistical analysis title
    OS (North America/EU)
    Comparison groups
    Carboplatin/Paclitaxel (C/P): North America/EU Population v C/P + MEDI-575 (C/P/M): North America/EU Population
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.315
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.4
    Statistical analysis title
    OS (Japan)
    Comparison groups
    Carboplatin/Paclitaxel (C/P): Japan Population v C/P + MEDI-575 (C/P/M): Japan Population
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    2.083
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    10.8

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (Total) Carboplatin/Paclitaxel + MEDI-575 (Total)
    Number of subjects analysed
    43
    53
    Units: participants
        Any AE
    42
    53
        Any SAE
    17
    25
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormalities in Laboratory Investigations Reported as Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Abnormalities in Laboratory Investigations Reported as Adverse Events (AEs) or Serious Adverse Events (SAEs)
    End point description
    Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs or SAEs were reported. The safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (Total) Carboplatin/Paclitaxel + MEDI-575 (Total)
    Number of subjects analysed
    43
    53
    Units: participants
        Anaemia
    15
    25
        Febrile neutropenia
    3
    6
        Idiopathic thrombocytopenic purpura
    0
    1
        Leukopenia
    2
    6
        Lymphadenopathy
    0
    2
        Lymphopenia
    2
    1
        Neutropenia
    7
    13
        Thrombocytopenia
    3
    10
        Activated partial thromboplastin time prolonged
    0
    1
        Haemoglobin decreased
    1
    5
        Lymphocyte count decreased
    0
    1
        Neutrophil count decreased
    5
    14
        Platelet count decreased
    5
    9
        White blood cell count decreased
    4
    10
        Alanine aminotransferase increased
    2
    5
        Aspartate aminotransferase increased
    3
    4
        Blood alkaline phosphatase increased
    2
    2
        Blood bilirubin increased
    2
    0
        Blood creatinine increased
    1
    3
        Blood magnesium decreased
    0
    1
        Gamma-glutamyl transferase increased
    0
    1
        Electrolyte imbalance
    1
    0
        Hypercholesterolaemia
    1
    0
        Hyperglycaemia
    5
    7
        Hypertriglyceridaemia
    2
    1
        Hypoalbuminaemia
    3
    7
        Hypocalcaemia
    3
    6
        Hypoglycaemia
    1
    1
        Hypokalemia
    8
    12
        Hypomagnesaemia
    10
    20
        Hyponatraemia
    4
    8
        Hypophosphataemia
    2
    4
        Iron deficiency
    0
    1
        Vitamin B12 deficiency
    0
    1
        Urine analysis abnormal
    0
    1
        Specific gravity urine increased
    0
    1
        Haematuria
    1
    1
        Proteinuria
    1
    1
        Pyelocaliectasis
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as AEs

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    End point title
    Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as AEs
    End point description
    The 12-lead ECG data were performed and obtained in triplicate that is 3 ECGs obtained within a 5 minute time period. Number of participants with ECG abnormalities were reported and recorded as AEs. The safety population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel (Total) Carboplatin/Paclitaxel + MEDI-575 (Total)
    Number of subjects analysed
    43
    53
    Units: participants
        Atrial fibrillation
    0
    1
        Atrial flutter
    0
    1
        Atrioventricular block first degree
    0
    1
        Myocardial infarction
    1
    0
        Tachycardia
    2
    3
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) for MEDI-575 After First Dose

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    End point title
    Maximum Observed Serum Concentration (Cmax) for MEDI-575 After First Dose
    End point description
    The Cmax refers to the highest measured drug concentration after a single dose which is obtained by collecting a series of blood samples and average of measuring the concentrations of drug in each sample. Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    4
    44
    Units: microgram per milliliter
        arithmetic mean (standard deviation)
    589.3 ± 175.6
    628.9 ± 441.8
    No statistical analyses for this end point

    Secondary: Time of Maximal Observed Concentration (Tmax) for MEDI-575 After First Dose

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    End point title
    Time of Maximal Observed Concentration (Tmax) for MEDI-575 After First Dose
    End point description
    The tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and average of measuring them for drug content. Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    4
    44
    Units: day
        arithmetic mean (standard deviation)
    0.044 ± 0.002
    0.046 ± 0.009
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau) for MEDI-575 After First Dose

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    End point title
    Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau) for MEDI-575 After First Dose
    End point description
    The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and average of measuring the concentrations of drug in each sample. AUCtau defined as area under the plasma concentration time profile from time zero to the end of the dosing interval (tau). Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    3
    40
    Units: microgram*day per milliliter
        arithmetic mean (standard deviation)
    3550 ± 496.1
    4803 ± 1948
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration at Steady State (Cmax,ss) for MEDI-575 After First Dose

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    End point title
    Maximum Serum Concentration at Steady State (Cmax,ss) for MEDI-575 After First Dose
    End point description
    Maximum serum concentration at steady state for MEDI-575 after first dose was calculated. Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion)
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    2
    27
    Units: microgram per milliliter
        arithmetic mean (standard deviation)
    2997 ± 2588
    619.7 ± 160.5
    No statistical analyses for this end point

    Secondary: Time to Maximum Serum Concentration at Steady State (Tmax,ss) for MEDI-575 After First Dose

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    End point title
    Time to Maximum Serum Concentration at Steady State (Tmax,ss) for MEDI-575 After First Dose
    End point description
    Time to maximum serum concentration at steady state for MEDI-575 after first dose was calculated. Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion)
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    2
    27
    Units: day
        arithmetic mean (standard deviation)
    0.042 ± 0.000
    0.049 ± 0.017
    No statistical analyses for this end point

    Secondary: Trough Serum Concentration at Steady State (Ctrough,ss) for MEDI-575 After First Dose

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    End point title
    Trough Serum Concentration at Steady State (Ctrough,ss) for MEDI-575 After First Dose
    End point description
    Trough serum concentration at steady state for MEDI-575 after first dose was calculated. Participants who were treated with MEDI-575 and for whom serum concentrations were available for PK data analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion)
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    2
    28
    Units: microgram per milliliter
        arithmetic mean (standard deviation)
    375 ± 155
    168 ± 75.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Positive Anti-MEDI-575 Antibodies

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    End point title
    Percentage of Participants With Positive Anti-MEDI-575 Antibodies
    End point description
    Immunogenicity assessment included determination of anti-drug (MEDI-575) antibodies in serum samples. The evaluable population included all participants who were treated with MEDI-575 and for whom at least one serum sample for immunogenicity testing was available.
    End point type
    Secondary
    End point timeframe
    Day 1 (prior to infusion) of Cycles 1 to 7 (21-day cycle), end of treatment, 30 and 60 days after the last dose (approximately 3 years)
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2
    Number of subjects analysed
    4
    49
    Units: percentage of participants
        number (not applicable)
    25.0
    26.5
    No statistical analyses for this end point

    Secondary: Number of Participants With Platelet-derived Growth Factor Receptor Alpha (PDGFRα) Expression in Tumor Cells of Archived Tumor Samples

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    End point title
    Number of Participants With Platelet-derived Growth Factor Receptor Alpha (PDGFRα) Expression in Tumor Cells of Archived Tumor Samples
    End point description
    The immunohistochemical expression of PDGFRα in tumor cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining tumor cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent). Evaluable populations for PDGFRα expression included all randomized participants who had formalin-fixed paraffin-embedded samples available at baseline and had positive-staining for tumor cells.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -28 to -1])
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2 Carboplatin/Paclitaxel - Phase 2
    Number of subjects analysed
    1
    5
    3
    Units: Participants
    number (not applicable)
        Intensity: 1+
    1
    2
    3
        Intensity: 2+
    0
    2
    0
        Intensity: 3+
    0
    1
    0
        Localization: cytoplasmic
    0
    3
    2
        Localization: membranous
    0
    2
    0
        Localization: nuclear
    1
    0
    1
        Frequency: rare
    1
    3
    1
        Frequency: occasional
    0
    0
    1
        Frequency: frequent
    0
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With PDGFRα Expression in Stromal Cells of Archived Tumor Samples

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    End point title
    Number of Participants With PDGFRα Expression in Stromal Cells of Archived Tumor Samples
    End point description
    The immunohistochemical expression of PDGFRα in stromal cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining stromal cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent). Evaluable populations for PDGFRα expression included all randomized participants who had formalin-fixed paraffin-embedded samples available at baseline and had positive-staining for tumor cells.
    End point type
    Secondary
    End point timeframe
    Baseline (Screening [Days -28 to -1])
    End point values
    Carboplatin/Paclitaxel + MEDI-575 - Phase 1b Carboplatin/Paclitaxel + MEDI-575 - Phase 2 Carboplatin/Paclitaxel - Phase 2
    Number of subjects analysed
    3
    16
    10
    Units: Participants
        Intensity: 1+
    2
    3
    3
        Intensity: 2+
    1
    10
    5
        Intensity: 3+
    0
    3
    2
        Localization: cytoplasmic
    3
    15
    10
        Localization: membranous
    0
    1
    0
        Localization: nuclear
    0
    0
    0
        Frequency: rare
    0
    3
    1
        Frequency: occasional
    1
    4
    3
        Frequency: frequent
    2
    9
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Carboplatin/Paclitaxel (Total)
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) or until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

    Reporting group title
    Carboplatin/Paclitaxel + MEDI-575 (Total)
    Reporting group description
    Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles. Participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575, MEDI-575 alone was continued until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal.

    Serious adverse events
    Carboplatin/Paclitaxel (Total) Carboplatin/Paclitaxel + MEDI-575 (Total)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 43 (39.53%)
    25 / 53 (47.17%)
         number of deaths (all causes)
    23
    35
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 53 (7.55%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopleural fistula
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         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 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 53 (7.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericolic abscess
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 53 (5.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Carboplatin/Paclitaxel (Total) Carboplatin/Paclitaxel + MEDI-575 (Total)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 43 (95.35%)
    53 / 53 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 43 (2.33%)
    7 / 53 (13.21%)
         occurrences all number
    1
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 43 (2.33%)
    10 / 53 (18.87%)
         occurrences all number
    4
    15
    Fatigue
         subjects affected / exposed
    23 / 43 (53.49%)
    31 / 53 (58.49%)
         occurrences all number
    35
    54
    Mucosal inflammation
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 53 (7.55%)
         occurrences all number
    1
    4
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 43 (0.00%)
    10 / 53 (18.87%)
         occurrences all number
    0
    12
    Pain
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 53 (7.55%)
         occurrences all number
    3
    4
    Pyrexia
         subjects affected / exposed
    4 / 43 (9.30%)
    7 / 53 (13.21%)
         occurrences all number
    4
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 53 (9.43%)
         occurrences all number
    2
    6
    Confusional state
         subjects affected / exposed
    1 / 43 (2.33%)
    6 / 53 (11.32%)
         occurrences all number
    1
    10
    Insomnia
         subjects affected / exposed
    3 / 43 (6.98%)
    9 / 53 (16.98%)
         occurrences all number
    3
    10
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 43 (2.33%)
    8 / 53 (15.09%)
         occurrences all number
    1
    8
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 43 (4.65%)
    5 / 53 (9.43%)
         occurrences all number
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 53 (7.55%)
         occurrences all number
    3
    9
    Haemoglobin decreased
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 53 (9.43%)
         occurrences all number
    1
    5
    Neutrophil count decreased
         subjects affected / exposed
    5 / 43 (11.63%)
    14 / 53 (26.42%)
         occurrences all number
    6
    29
    Platelet count decreased
         subjects affected / exposed
    5 / 43 (11.63%)
    9 / 53 (16.98%)
         occurrences all number
    13
    22
    Weight decreased
         subjects affected / exposed
    3 / 43 (6.98%)
    14 / 53 (26.42%)
         occurrences all number
    3
    17
    White blood cell count decreased
         subjects affected / exposed
    4 / 43 (9.30%)
    10 / 53 (18.87%)
         occurrences all number
    5
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 43 (32.56%)
    24 / 53 (45.28%)
         occurrences all number
    28
    73
    Leukopenia
         subjects affected / exposed
    2 / 43 (4.65%)
    6 / 53 (11.32%)
         occurrences all number
    6
    23
    Neutropenia
         subjects affected / exposed
    6 / 43 (13.95%)
    12 / 53 (22.64%)
         occurrences all number
    9
    37
    Thrombocytopenia
         subjects affected / exposed
    3 / 43 (6.98%)
    10 / 53 (18.87%)
         occurrences all number
    3
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 43 (13.95%)
    10 / 53 (18.87%)
         occurrences all number
    6
    10
    Dyspnoea
         subjects affected / exposed
    6 / 43 (13.95%)
    11 / 53 (20.75%)
         occurrences all number
    6
    18
    Haemoptysis
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 53 (9.43%)
         occurrences all number
    1
    6
    Hiccups
         subjects affected / exposed
    3 / 43 (6.98%)
    5 / 53 (9.43%)
         occurrences all number
    3
    7
    Productive cough
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 53 (5.66%)
         occurrences all number
    6
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 43 (6.98%)
    6 / 53 (11.32%)
         occurrences all number
    4
    7
    Dysgeusia
         subjects affected / exposed
    1 / 43 (2.33%)
    12 / 53 (22.64%)
         occurrences all number
    1
    12
    Headache
         subjects affected / exposed
    4 / 43 (9.30%)
    7 / 53 (13.21%)
         occurrences all number
    4
    9
    Neuropathy peripheral
         subjects affected / exposed
    11 / 43 (25.58%)
    18 / 53 (33.96%)
         occurrences all number
    16
    44
    Paraesthesia
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 53 (9.43%)
         occurrences all number
    1
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    13 / 43 (30.23%)
    14 / 53 (26.42%)
         occurrences all number
    21
    24
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 43 (4.65%)
    10 / 53 (18.87%)
         occurrences all number
    2
    12
    Constipation
         subjects affected / exposed
    13 / 43 (30.23%)
    13 / 53 (24.53%)
         occurrences all number
    16
    16
    Diarrhoea
         subjects affected / exposed
    8 / 43 (18.60%)
    24 / 53 (45.28%)
         occurrences all number
    11
    49
    Dyspepsia
         subjects affected / exposed
    4 / 43 (9.30%)
    7 / 53 (13.21%)
         occurrences all number
    4
    7
    Nausea
         subjects affected / exposed
    22 / 43 (51.16%)
    27 / 53 (50.94%)
         occurrences all number
    30
    41
    Stomatitis
         subjects affected / exposed
    3 / 43 (6.98%)
    3 / 53 (5.66%)
         occurrences all number
    5
    4
    Vomiting
         subjects affected / exposed
    8 / 43 (18.60%)
    14 / 53 (26.42%)
         occurrences all number
    11
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 43 (48.84%)
    29 / 53 (54.72%)
         occurrences all number
    27
    38
    Rash
         subjects affected / exposed
    4 / 43 (9.30%)
    5 / 53 (9.43%)
         occurrences all number
    4
    5
    Rash maculo-papular
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 53 (5.66%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 43 (4.65%)
    11 / 53 (20.75%)
         occurrences all number
    2
    18
    Arthralgia
         subjects affected / exposed
    13 / 43 (30.23%)
    22 / 53 (41.51%)
         occurrences all number
    22
    35
    Bone pain
         subjects affected / exposed
    4 / 43 (9.30%)
    3 / 53 (5.66%)
         occurrences all number
    4
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Myalgia
         subjects affected / exposed
    14 / 43 (32.56%)
    17 / 53 (32.08%)
         occurrences all number
    25
    33
    Pain in extremity
         subjects affected / exposed
    6 / 43 (13.95%)
    8 / 53 (15.09%)
         occurrences all number
    6
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 43 (25.58%)
    27 / 53 (50.94%)
         occurrences all number
    22
    50
    Dehydration
         subjects affected / exposed
    6 / 43 (13.95%)
    7 / 53 (13.21%)
         occurrences all number
    7
    10
    Hyperglycaemia
         subjects affected / exposed
    5 / 43 (11.63%)
    7 / 53 (13.21%)
         occurrences all number
    7
    12
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    7 / 53 (13.21%)
         occurrences all number
    4
    9
    Hypocalcaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    6 / 53 (11.32%)
         occurrences all number
    4
    9
    Hypokalaemia
         subjects affected / exposed
    8 / 43 (18.60%)
    12 / 53 (22.64%)
         occurrences all number
    9
    19
    Hypomagnesaemia
         subjects affected / exposed
    10 / 43 (23.26%)
    20 / 53 (37.74%)
         occurrences all number
    14
    42
    Hyponatraemia
         subjects affected / exposed
    4 / 43 (9.30%)
    8 / 53 (15.09%)
         occurrences all number
    4
    11
    Hypophosphataemia
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    9 / 43 (20.93%)
    4 / 53 (7.55%)
         occurrences all number
    11
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2010
    The protocol was amended for the modification of sample size and defining cohorts, participating sites were increased in Japanese sites, randomization criteria in North America/EU cohort and Japanese cohort were defined, clarification was provided for a cap on squamous cell histology and if subject experiences dose-limiting toxicity (DLT) due to MEDI-575 in the first 21-day cycle were provided, safety reporting procedures in Japan were added, inclusion and exclusion criteria were revised, information regarding the potential for a drug-drug interaction with CYP2C8 and CYP3A4 inhibitors and inducers (per the approved labeling for paclitaxel) was added, , updated population analysis definitions, clarifications for the administration of carboplatin/paclitaxel and MEDI-575 and analyses methods for objective response rate (ORR) and change in tumor size were included and confirmed that primary endpoint of progression-free survival (PFS) would only be in the North America/EU cohort.
    10 Feb 2012
    The protocol was amended for the modification of inclusion and withdrawal criteria, treatment administration, storage, and handling details were added, Preparation of Investigational Product at the site was updated (once prepared, MEDI-575 had to be used within 6 hours or discarded as it does not contain a preservative), Safety follow-up post last dose was increased from 60 to 90 days, and Data Safety Monitoring Board was added.
    09 May 2012
    The protocol was amended to remove primary endpoint of progression-free survival (PFS) as reference to a blinded central review of imaging data, NSCLC histology was removed as a stratification factor, MEDI-575 serum concentration and ADA assessments were removed from the 3-month post last treatment visit, Subgroup analysis for each NSCLC histology type was changed to be performed for each of the antitumor activity endpoints (PFS, ORR, DR, TTP, TTR, and OS) and Inclusion Criterion was revised.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    13 Jul 2012
    Sponsor voluntarily suspended enrollment into this study based on safety issues observed across multiple studies in the MEDI-575 program and no suggestion of improved efficacy versus the control group in this specific study. MedImmune’s Safety Monitoring Committee (SMC) recommended that the trial not be re-opened to enrollment. Subjects were continued to be followed until 04Sep2013 at which time the study was closed.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In conjunction with the overall risk-benefit assessment, study was terminated prematurely due to safety concerns. Change in tumor size outcome measure was not analyzed as per changed planned analysis due to premature termination of the study.
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