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    Clinical Trial Results:
    AIPAC (Active Immunotherapy PAClitaxel): A multicentre, Phase IIb, randomised, double blind, placebo-controlled study in hormone receptor-positive metastatic breast carcinoma patients receiving IMP321 (LAG-3Ig fusion protein) or placebo as adjunctive to a standard chemotherapy treatment regimen of paclitaxel.

    Summary
    EudraCT number
    		 2015-002541-63
    Trial protocol
    		 NL   BE   HU   FR   DE   PL   GB  
    Global end of trial date
    14 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2022
    First version publication date
    09 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IMP321-P011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02614833
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Immutep S.A.S
    Sponsor organisation address
    21 rue Jean Rostand, Orsay Cedex, France, 91893
    Public contact
    Clinical Trial Disclosure Enquiries, Immutep S.A.S, +33 146835822, enquiries@immutep.com
    Scientific contact
    Clinical Trial Disclosure Enquiries, Immutep S.A.S, +33 146835822, enquiries@immutep.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
    28 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of efti combined with weekly paclitaxel compared to weekly paclitaxel plus placebo in hormone receptor-positive metastatic breast cancer subjects.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. Throughout the Randomisation stage of the study, an Independent Data Monitoring Committee (IDMC) monitored subject safety, survival rates and demographics at regular intervals and had the possibility to convene ad hoc upon the request of the PI, Medical Monitor or Sponsor and in accordance with the IDMC charter. During the randomised, placebo-controlled stage of this study, the IDMC received tables, listings and figures per treatment arm. The IDMC received reports of all adverse events (AEs) by system organ class. The IDMC had the authority to recommend any dose de-escalation steps, if needed or stopping the study if at any time during the study unacceptable AEs or safety concerns related to the study treatment occurred.
    Background therapy
    		 Paclitaxel was given in both treatment arms. The Randomisation Stage (Stage 2) was a randomised, placebo-controlled and double-blind stage. The study design and conduct followed the ‘Note for Guidance on evaluation of anti-cancer medicinal products in man’ (EMA/CHMP/205/95/rev.4). All subjects received standard-of-care weekly paclitaxel to be ethically treated for the disease. Subjects received weekly paclitaxel instead of every three weeks because this has been observed to result in higher efficacy and less toxicity. Weekly Paclitaxel has become a standard of care administration schedule since more than 15 years ago.
    Evidence for comparator
    		 In this study the use of a placebo associated with double blinding greatly improve the quality of the data and its interpretation. It therefore alleviates many of the statistical biases observed in open label phase II studies. It hence also requires that one of the study arms receives placebo rather than just simply prohibiting the use of endocrine therapy subsequently to termination of the chemoimmunotherapy stage in this arm.
    Actual start date of recruitment
    12 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 35
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Belgium: 88
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 12
    Worldwide total number of subjects
    226
    EEA total number of subjects
    198
    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)
    147
    From 65 to 84 years
    78
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The 1st ICF for the randomisation stage was signed on 06Jan2017. 32 sites in 7 countries. Number of sites per country: 9 BE, 3 FR, 5 DE, 2 HU, 8 NL, 2 PL, 3 UK

    Pre-assignment
    Screening details
    		 Subjects with hormone receptor positive (HR+), HER2 negative metastatic breast cancer eligible to weekly paclitaxel. Randomisation Stage: 277 subjects screened, 50 subjects screen failures. 1 subject randomised, but subject did not receive drug

    Period 1
    Period 1 title
    Randomisation stage (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The Randomisation stage used a double-blind design with regard to the subjects and the Investigators, research staff at the site and sponsor staff, in order to eliminate systematic observer or performance bias. Unblinding of the Investigator was only allowed in case of emergency. To avoid unblinding, staff of the Immutep S.A.S. lab did not have access to the eCRF nor attended any meeting where subject data were discussed until unblinding for primary analysis occured.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Paclitaxel + Placebo
    Arm description
    		 Placebo Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + placebo in a double-blinded fashion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to IMP321
    Investigational medicinal product code
    Placebo to IMP321
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo drug product matched the appearance and injection characteristics of efti drug product and comprised efti formulation buffer. The placebo drug product is a single-use, preservative-free, sterile solution for subcutaneous injections. Preparation of study drug was done according to the Investigational Medicinal Product (IMP) Handling Manual. The placebo was administered via subcutaneous injection (single anatomical site) on the anterior face of the thigh. Repeated s.c. doses of the placebo were administered on Day 2 and Day 16 of each 4-week cycle during the 6 cycles of weekly paclitaxel chemotherapy (chemo-immunotherapy phase). After completion of this chemo-immunotherapy phase, responding or stable subjects received study agent (i.e. without paclitaxel) every 4 weeks during the maintenance phase for an additional 12 injections.

    Arm title
    		 Paclitaxel + 30 mg efti
    Arm description
    		 30 mg Efti Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + 30 mg Efti
    Arm type
    		 Experimental

    Investigational medicinal product name
    IMP321
    Investigational medicinal product code
    IMP321
    Other name
    eftilagimod alfa
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Efti drug product is a single-use, preservative-free, sterile solution of efti for subcutaneous injections. Preparation of study drug was done according to the Investigational Medicinal Product (IMP) Handling Manual. The 30 mg dose of efti was administered via subcutaneous injection (single anatomical site) on the anterior face of the thigh. Repeated s.c. doses of efti were administered on Day 2 and Day 16 of each 4-week cycle during the 6 cycles of weekly paclitaxel chemotherapy (chemo-immunotherapy phase). After completion of this chemo-immunotherapy phase, responding or stable subjects received study agent (i.e. without paclitaxel) every 4 weeks during the maintenance phase for an additional 12 injections.

    Number of subjects in period 1
    		Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Started
    112
    114
    Randomisation Stage - Maintenance
    54
    60
    Completed
    2
    2
    Not completed
    110
    112
         Adverse event, serious fatal
    1
    1
         Physician decision
    3
    2
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    9
    7
         Symptomatic deterioration
    5
    5
         1 Euthanasia + 1 Long Treatment Delay
    -
    2
         Sponsor´s decision
    1
    -
         Disease Progression
    90
    92

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paclitaxel + Placebo
    Reporting group description
    		 Placebo Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + placebo in a double-blinded fashion

    Reporting group title
    Paclitaxel + 30 mg efti
    Reporting group description
    		 30 mg Efti Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + 30 mg Efti

    Reporting group values
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti Total
    Number of subjects
    		 112 114 226
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 71 76 147
        From 65-87 years
    		 41 38 79
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.3 ± 11.36 58.0 ± 11.93 -
    Gender categorical
    Units: Subjects
        Female
    		 112 114 226
        Male
    		 0 0 0
    ECOG at Baseline
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 70 69 139
        ECOG 1
    		 42 44 86
        ECOG 2
    		 0 1 1
    Visceral Disease
    Disease Overview Per Treatment Group at Baseline: Visceral Disease
    Units: Subjects
        Visceral Disease - Yes
    		 104 103 207
        Visceral Disease - No
    		 8 11 19
    Breast Cancer Subtype
    Breast Cancer Subtype – Retrospective Central Assessment The central pathology laboratory applied immunohistochemistry to confirm HR positivity, Ki-67 status, and HER2-neu status. Fluorescence in situ hybridisation analysis was performed on samples yielding positive HER2-neu result on immunohistochemistry.
    Units: Subjects
        no result
    		 25 32 57
        Luminal A
    		 32 28 60
        Luminal B
    		 43 40 83
        Luminal undefined
    		 4 8 12
        Triple negative
    		 1 1 2
        Undefined
    		 6 5 11
        HER2 positive
    		 1 0 1
    Number of Disease Sites at Screening
    Number of Disease Sites at Screening
    Units: Subjects
        1-2 disease sites
    		 34 46 80
        >2 disease sites
    		 78 68 146
    Location of Disease at Screening Bone
    Location of Disease at Screening
    Units: Subjects
        Bone
    		 82 83 165
        not Bone
    		 30 31 61
    Location of Disease at Screening Liver
    Location of Disease at Screening Liver
    Units: Subjects
        Liver
    		 85 80 165
        not Liver
    		 27 34 61
    Location of Disease at Screening Lymph Node
    Location of Disease at Screening Lymph Node
    Units: Subjects
        Lymph node
    		 56 57 113
        not Lymph node
    		 56 57 113
    Biomarker CA 15-3
    Biomarker CA 15-3
    Units: Subjects
        <30 arb units/L
    		 20 19 39
        ≥30 arb units/L
    		 88 92 180
        not recorded
    		 4 3 7
    Lactate Dehydrogenase at Baseline
    Lactate Dehydrogenase at Baseline
    Units: Subjects
        Elevated (>250 U/L)
    		 81 74 155
        Non-Elevated ( ≤250 U/L)
    		 30 39 69
        not recorded
    		 1 1 2
    Monocytes at Baseline
    Units: Subjects
        <0.25 x 109 cells/L
    		 22 25 47
        ≥0.25 x 109 cells/L
    		 89 89 178
        not recorded
    		 1 0 1
    Time Between Metastatic Stage 4 Diagnosis and Informed Consent (days)
    Time Between Metastatic Stage 4 Diagnosis and Informed Consent (days)
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 668.0 (55 to 1070) 262.5 (39 to 824) -
    Body Mass Index
    Units: kg/m2
        median (full range (min-max))
    		 24.9 (15.4 to 44.5) 24.7 (18.1 to 48.1) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all assigned/randomised subjects who received at least one dose of study drug (i.e., one dose of paclitaxel or one dose of efti or placebo). Subjects in this population were analysed according the treatment to which they were randomised. This population is the primary population for the analyses of efficacy endpoints.

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    226
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    147
        From 65-87 years
    79
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.0 ± 11.93
    Gender categorical
    Units: Subjects
        Female
    114
        Male
    0
    ECOG at Baseline
    ECOG performance status
    Units: Subjects
        ECOG 0
    139
        ECOG 1
    86
        ECOG 2
    1
    Visceral Disease
    Disease Overview Per Treatment Group at Baseline: Visceral Disease
    Units: Subjects
        Visceral Disease - Yes
    207
        Visceral Disease - No
    19
    Breast Cancer Subtype
    Breast Cancer Subtype – Retrospective Central Assessment The central pathology laboratory applied immunohistochemistry to confirm HR positivity, Ki-67 status, and HER2-neu status. Fluorescence in situ hybridisation analysis was performed on samples yielding positive HER2-neu result on immunohistochemistry.
    Units: Subjects
        no result
    57
        Luminal A
    60
        Luminal B
    83
        Luminal undefined
    12
        Triple negative
    2
        Undefined
    11
        HER2 positive
    1
    Number of Disease Sites at Screening
    Number of Disease Sites at Screening
    Units: Subjects
        1-2 disease sites
    80
        >2 disease sites
    146
    Location of Disease at Screening Bone
    Location of Disease at Screening
    Units: Subjects
        Bone
    165
        not Bone
    61
    Location of Disease at Screening Liver
    Location of Disease at Screening Liver
    Units: Subjects
        Liver
    165
        not Liver
    61
    Location of Disease at Screening Lymph Node
    Location of Disease at Screening Lymph Node
    Units: Subjects
        Lymph node
    113
        not Lymph node
    113
    Biomarker CA 15-3
    Biomarker CA 15-3
    Units: Subjects
        <30 arb units/L
    39
        ≥30 arb units/L
    180
        not recorded
    7
    Lactate Dehydrogenase at Baseline
    Lactate Dehydrogenase at Baseline
    Units: Subjects
        Elevated (>250 U/L)
    155
        Non-Elevated ( ≤250 U/L)
    69
        not recorded
    2
    Monocytes at Baseline
    Units: Subjects
        <0.25 x 109 cells/L
    47
        ≥0.25 x 109 cells/L
    178
        not recorded
    1
    Time Between Metastatic Stage 4 Diagnosis and Informed Consent (days)
    Time Between Metastatic Stage 4 Diagnosis and Informed Consent (days)
    Units: days
        median (inter-quartile range (Q1-Q3))
    741.8 (41 to 944)
    Body Mass Index
    Units: kg/m2
        median (full range (min-max))
    24.7 (15.4 to 48.1)

    End points

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    End points reporting groups
    Reporting group title
    Paclitaxel + Placebo
    Reporting group description
    		 Placebo Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + placebo in a double-blinded fashion

    Reporting group title
    Paclitaxel + 30 mg efti
    Reporting group description
    		 30 mg Efti Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + 30 mg Efti

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all assigned/randomised subjects who received at least one dose of study drug (i.e., one dose of paclitaxel or one dose of efti or placebo). Subjects in this population were analysed according the treatment to which they were randomised. This population is the primary population for the analyses of efficacy endpoints.

    Primary: Progression-free survival (PFS) - BICR

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    End point title
    		 Progression-free survival (PFS) - BICR
    End point description
    PFS was defined as the number of days between the start date of Randomisation and the earliest date of documented disease progression, as defined by RECIST V1.1, or death without prior progression. For primary analysis an independent blinded review was performed, i.e., all imaging time points were reviewed by two independent reviewers according to RECIST 1.1. In case of discrepancy, a third reader (adjudicator) reviewed the images. Analysis incl. full analysis set.
    End point type
    Primary
    End point timeframe
    PFS will be calculated as the time from the date of randomisation to the date of first documentation of disease progression (RECIST1.1) or date of death due to any cause, whichever occurs first.
    End point values
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Number of subjects analysed
    112
    114
    Units: month
        median (confidence interval 95%)
    7.29 (5.52 to 7.46)
    7.29 (6.64 to 7.46)
    Statistical analysis title
    		 Progression-Free Survival (BICR)
    Comparison groups
    Paclitaxel + Placebo v Paclitaxel + 30 mg efti
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.341 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.3
    Variability estimate
    Standard deviation
    Notes
    [1] - stratified by ECOG (0 versus 1)

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    OS was defined as the time between the date of the date of Randomisation and the date of death. For subjects without documentation of death, OS was censored on the last date the subject was known to be alive.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is defined as the time between the date of randomisation and the date of death from any cause.
    End point values
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Number of subjects analysed
    112
    114
    Units: month
        median (confidence interval 95%)
    17.54 (12.91 to 21.85)
    20.37 (14.26 to 25.07)
    Statistical analysis title
    		 Statistical Analysis OS
    Comparison groups
    Paclitaxel + Placebo v Paclitaxel + 30 mg efti
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.197
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.19
    Variability estimate
    Standard deviation

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective Response Rate (ORR) according to RECIST V1.1
    End point type
    Secondary
    End point timeframe
    Radiological assessments according to RECIST 1.1. from screening onwards every 8 weeks until week 73, every 12 weeks thereafter.
    End point values
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Number of subjects analysed
    112
    114
    Units: percent
        number (confidence interval 95%)
    40.6 (31 to 51)
    51.4 (42 to 61)
    Statistical analysis title
    		 Overall Response Rate
    Comparison groups
    Paclitaxel + 30 mg efti v Paclitaxel + Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.118
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in proportion
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 24
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening and then at each visit until end of PFS and OS follow up (every 12 weeks after end of treatment).
    Adverse event reporting additional description
    According to NCI CTCAE V4.03. Reporting from ICF signature until 30 days after last study agent administration. Safety follow-up is to be performed until resolution of AEs/SAEs or for a minimum of 2 months after last study agent administration or until subject is receiving any other anti-cancer therapy or any other investigational therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Paclitaxel + Placebo
    Reporting group description
    		 Placebo Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + placebo in a double-blinded fashion.

    Reporting group title
    Paclitaxel + 30 mg efti
    Reporting group description
    		 30 mg Efti Arm: Paclitaxel (80 mg/m2 Day 1, 8 and 15 every 4 weeks [1 cycle] for maximum of 6 cycles) + efti 30mg in a double-blinded fashion

    Serious adverse events
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 112 (19.64%)
    22 / 114 (19.30%)
         number of deaths (all causes)
    83
    81
         number of deaths resulting from adverse events
    3
    2
    Surgical and medical procedures
    Thoracic outlet surgery
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast reconstruction
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopaedic procedure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 112 (0.00%)
    5 / 114 (4.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injection related reaction
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         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 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatobiliary disease
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    2 / 112 (1.79%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Paclitaxel + Placebo Paclitaxel + 30 mg efti
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 112 (100.00%)
    114 / 114 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 112 (9.82%)
    14 / 114 (12.28%)
         occurrences all number
    47
    38
    Hot flush
         subjects affected / exposed
    3 / 112 (2.68%)
    6 / 114 (5.26%)
         occurrences all number
    4
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    55 / 112 (49.11%)
    53 / 114 (46.49%)
         occurrences all number
    85
    104
    Injection site reaction
         subjects affected / exposed
    4 / 112 (3.57%)
    39 / 114 (34.21%)
         occurrences all number
    8
    123
    Injection site erythema
         subjects affected / exposed
    2 / 112 (1.79%)
    35 / 114 (30.70%)
         occurrences all number
    2
    101
    Oedema peripheral
         subjects affected / exposed
    19 / 112 (16.96%)
    8 / 114 (7.02%)
         occurrences all number
    29
    12
    Pyrexia
         subjects affected / exposed
    8 / 112 (7.14%)
    17 / 114 (14.91%)
         occurrences all number
    10
    38
    Injection site pain
         subjects affected / exposed
    6 / 112 (5.36%)
    12 / 114 (10.53%)
         occurrences all number
    10
    23
    Influenza like illness
         subjects affected / exposed
    4 / 112 (3.57%)
    10 / 114 (8.77%)
         occurrences all number
    4
    15
    Injection site induration
         subjects affected / exposed
    0 / 112 (0.00%)
    9 / 114 (7.89%)
         occurrences all number
    0
    15
    Pain
         subjects affected / exposed
    0 / 112 (0.00%)
    9 / 114 (7.89%)
         occurrences all number
    0
    11
    Injection site swelling
         subjects affected / exposed
    0 / 112 (0.00%)
    7 / 114 (6.14%)
         occurrences all number
    0
    17
    Chest pain
         subjects affected / exposed
    6 / 112 (5.36%)
    6 / 114 (5.26%)
         occurrences all number
    8
    6
    Chills
         subjects affected / exposed
    3 / 112 (2.68%)
    6 / 114 (5.26%)
         occurrences all number
    3
    9
    Malaise
         subjects affected / exposed
    7 / 112 (6.25%)
    4 / 114 (3.51%)
         occurrences all number
    7
    5
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    10 / 112 (8.93%)
    16 / 114 (14.04%)
         occurrences all number
    11
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 112 (19.64%)
    20 / 114 (17.54%)
         occurrences all number
    24
    22
    Dyspnoea
         subjects affected / exposed
    20 / 112 (17.86%)
    16 / 114 (14.04%)
         occurrences all number
    31
    20
    Epistaxis
         subjects affected / exposed
    8 / 112 (7.14%)
    8 / 114 (7.02%)
         occurrences all number
    11
    9
    Dyspnoea exertional
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 114 (1.75%)
         occurrences all number
    6
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 112 (8.93%)
    9 / 114 (7.89%)
         occurrences all number
    10
    11
    Anxiety
         subjects affected / exposed
    8 / 112 (7.14%)
    4 / 114 (3.51%)
         occurrences all number
    8
    4
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    34 / 112 (30.36%)
    25 / 114 (21.93%)
         occurrences all number
    56
    36
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 112 (16.07%)
    16 / 114 (14.04%)
         occurrences all number
    26
    39
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 112 (10.71%)
    10 / 114 (8.77%)
         occurrences all number
    18
    33
    Blood alkaline phosphatase increased
         subjects affected / exposed
    14 / 112 (12.50%)
    9 / 114 (7.89%)
         occurrences all number
    15
    13
    White blood cell count decreased
         subjects affected / exposed
    11 / 112 (9.82%)
    5 / 114 (4.39%)
         occurrences all number
    28
    8
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 112 (6.25%)
    3 / 114 (2.63%)
         occurrences all number
    8
    5
    Neutrophil count decreased
         subjects affected / exposed
    6 / 112 (5.36%)
    2 / 114 (1.75%)
         occurrences all number
    9
    4
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    28 / 112 (25.00%)
    23 / 114 (20.18%)
         occurrences all number
    53
    31
    Headache
         subjects affected / exposed
    17 / 112 (15.18%)
    21 / 114 (18.42%)
         occurrences all number
    19
    24
    Peripheral sensory neuropathy
         subjects affected / exposed
    22 / 112 (19.64%)
    21 / 114 (18.42%)
         occurrences all number
    47
    36
    Paraesthesia
         subjects affected / exposed
    16 / 112 (14.29%)
    14 / 114 (12.28%)
         occurrences all number
    27
    23
    Dysgeusia
         subjects affected / exposed
    12 / 112 (10.71%)
    7 / 114 (6.14%)
         occurrences all number
    13
    7
    Dizziness
         subjects affected / exposed
    7 / 112 (6.25%)
    6 / 114 (5.26%)
         occurrences all number
    9
    7
    Polyneuropathy
         subjects affected / exposed
    5 / 112 (4.46%)
    6 / 114 (5.26%)
         occurrences all number
    5
    8
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    21 / 112 (18.75%)
    22 / 114 (19.30%)
         occurrences all number
    46
    39
    Anaemia
         subjects affected / exposed
    16 / 112 (14.29%)
    18 / 114 (15.79%)
         occurrences all number
    26
    39
    Leukopenia
         subjects affected / exposed
    6 / 112 (5.36%)
    3 / 114 (2.63%)
         occurrences all number
    10
    8
    Gastrointestinal disorders
    Asthenia
         subjects affected / exposed
    20 / 112 (17.86%)
    16 / 114 (14.04%)
         occurrences all number
    35
    29
    Nausea
         subjects affected / exposed
    40 / 112 (35.71%)
    44 / 114 (38.60%)
         occurrences all number
    55
    81
    Diarrhoea
         subjects affected / exposed
    41 / 112 (36.61%)
    33 / 114 (28.95%)
         occurrences all number
    60
    59
    Constipation
         subjects affected / exposed
    20 / 112 (17.86%)
    20 / 114 (17.54%)
         occurrences all number
    23
    26
    Abdominal pain
         subjects affected / exposed
    11 / 112 (9.82%)
    17 / 114 (14.91%)
         occurrences all number
    14
    26
    Vomiting
         subjects affected / exposed
    13 / 112 (11.61%)
    17 / 114 (14.91%)
         occurrences all number
    19
    23
    Abdominal pain upper
         subjects affected / exposed
    11 / 112 (9.82%)
    10 / 114 (8.77%)
         occurrences all number
    13
    13
    Stomatitis
         subjects affected / exposed
    6 / 112 (5.36%)
    8 / 114 (7.02%)
         occurrences all number
    11
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 114 (5.26%)
         occurrences all number
    3
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    56 / 112 (50.00%)
    46 / 114 (40.35%)
         occurrences all number
    84
    67
    Rash
         subjects affected / exposed
    12 / 112 (10.71%)
    12 / 114 (10.53%)
         occurrences all number
    20
    16
    Dry skin
         subjects affected / exposed
    5 / 112 (4.46%)
    8 / 114 (7.02%)
         occurrences all number
    5
    8
    Nail disorder
         subjects affected / exposed
    8 / 112 (7.14%)
    8 / 114 (7.02%)
         occurrences all number
    11
    10
    Pruritus
         subjects affected / exposed
    7 / 112 (6.25%)
    6 / 114 (5.26%)
         occurrences all number
    20
    6
    Erythema
         subjects affected / exposed
    10 / 112 (8.93%)
    5 / 114 (4.39%)
         occurrences all number
    11
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 112 (11.61%)
    14 / 114 (12.28%)
         occurrences all number
    18
    16
    Pain in extremity
         subjects affected / exposed
    8 / 112 (7.14%)
    14 / 114 (12.28%)
         occurrences all number
    10
    22
    Back pain
         subjects affected / exposed
    16 / 112 (14.29%)
    13 / 114 (11.40%)
         occurrences all number
    22
    21
    Myalgia
         subjects affected / exposed
    12 / 112 (10.71%)
    10 / 114 (8.77%)
         occurrences all number
    20
    14
    Musculoskeletal pain
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 114 (5.26%)
         occurrences all number
    2
    7
    Bone pain
         subjects affected / exposed
    9 / 112 (8.04%)
    4 / 114 (3.51%)
         occurrences all number
    10
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    11 / 112 (9.82%)
    11 / 114 (9.65%)
         occurrences all number
    13
    13
    Nasopharyngitis
         subjects affected / exposed
    16 / 112 (14.29%)
    7 / 114 (6.14%)
         occurrences all number
    18
    8
    Rhinitis
         subjects affected / exposed
    4 / 112 (3.57%)
    7 / 114 (6.14%)
         occurrences all number
    4
    9
    Cystitis
         subjects affected / exposed
    2 / 112 (1.79%)
    6 / 114 (5.26%)
         occurrences all number
    2
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 112 (12.50%)
    16 / 114 (14.04%)
         occurrences all number
    16
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Nov 2016
    • Primary analysis and long-term follow-up for OS was introduced; • Clarification on treatment/study duration, radiological assessments, contraception, subject criteria, safety reporting and dose adjustments of paclitaxel were given to harmonise between participating countries
    10 May 2017
    • Clarification on timing of radiological assessments, contraception method, safety reporting, statistical methods and analyses populations was given.
    16 Jan 2018
    • General update (contact details, table of content, abbreviations, references, footnotes, appendices linguistic improvements); • Clarification of inclusion and exclusion criteria incl. details on contraception; • Clarifications on study objectives, endpoints and study design including treatment and assessments; • Clarifications on study duration; • Clarification on safety reporting; • Clarification on statistical assumptions, sample size increase and specification of statistical analyses
    12 Mar 2018
    • General update (typographical corrections, clarifications, vendor contact details, update on clinical data of efti, update of link to RECIST V1.1 guidelines) • Update to study duration • Clarification on HBV screening requirements; • Explanation on the sequence of primary endpoint analysis; • Addition of two hypersensitivity reactions reported from the efti-P011 study added and related risk language updated; • Addition of management and discontinuation guidelines for hypersensitivity reactions; • Inclusion of local best clinical practice into assessment of safety criteria prior to paclitaxel administration

    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.
    EudraCT results platform is not built to accommodate two stage trials. Results of the randomisation stage are presented in EudraCT. Early conclusion of overall survival follow up due to data maturity.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30977393
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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