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    Clinical Trial Results:
    DETECT III – A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus Lapatinib in patients with initially HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells

    Summary
    EudraCT number
    		 2010-024238-46
    Trial protocol
    		 DE  
    Global end of trial date
    20 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2024
    First version publication date
    10 May 2024
    Other versions
    Summary report(s)
    		 Müller et al. 2021_ESMO_prognostic relevance of HER2 status
    Fehm et. al_ClinChem_2024

    Trial information

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    Trial identification
    Sponsor protocol code
    D-III
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01619111
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinik Ulm
    Sponsor organisation address
    Albert-Einstein-Allee 29, Ulm, Germany, 89075
    Public contact
    Studienzentrale , Universitätsklinikum Ulm - Klinik für Frauenheilkunde und Geburtshilfe, 0049 73150058652, Studienzentrale.UFK@uniklinik-ulm.de
    Scientific contact
    Prof. Wolfgang Janni, Universitätsklinikum Ulm - Klinik für Frauenheilkunde und Geburtshilfe, 3150058652 73150058652, Studienzentrale.UFK@uniklinik-ulm.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to prove the clinical efficacy of lapatinib (as assessed by the CTC clearance rate) in patients with metastasizing breast cancer who exhibit HER2-positive circulating tumor cells (CTC) although the primary tumor tissue and/or biopsies from metastatic sites were investigated for HER2 status and showed HER2-negativity.
    Protection of trial subjects
    Safety and tolerability were assessed by evaluation of adverse event (AE) and serious adverse event (SAE) reports using the international Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The safety population (which is equivalent to mITT population) comprised all randomized subjects who received at least one dose of the respective study treatment.
    Background therapy
    		 Reference therapy was standard therapy, to be selected from the mono-chemotherapies or endocrine therapies
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    101
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with HER2-neg. metastatic breast cancer,

    Pre-assignment
    Screening details
    		 positive HER2-status of circulating tumor cells (CTCs)

    Pre-assignment period milestones
    Number of subjects started
    		 101
    Number of subjects completed
    		 101

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Therapy plus Lapatinib
    Arm description
    		 Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib Tyverb
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    daily dose of lapatinib may have been adjusted dependent on the dose regimen of the standard chemo- or endocrine therapy and on the occurrence of adverse events. In any case, the maximum daily dose was 1500 mg, the minimum daily dose was 750 mg. Duration of lapatinib therapy was 12 months

    Arm title
    		 Standard therapy
    Arm description
    		 During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not
    Arm type
    		 Standard therapy

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Standard Therapy plus Lapatinib Standard therapy
    Started
    53
    48
    Completed
    53
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Therapy plus Lapatinib
    Reporting group description
    		 Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol).

    Reporting group title
    Standard therapy
    Reporting group description
    		 During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not

    Reporting group values
    		 Standard Therapy plus Lapatinib Standard therapy Total
    Number of subjects
    		 53 48 101
    Age categorical
    total iTT population n = 101 median age 59 (26-80)
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 53 48 101
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 59 ( 0 ) 58 ( 0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 53 48 101
        Male
    		 0 0 0
    CTC clearence rate (at the time of first CTC assessment and survival)
    CTC clearance rates at the time of first CTC assessment and survival
    Units: Subjects
        CTC clearance
    		 53 48 101
    CTC clearance rate (after study treatment and survival)
    Units: Subjects
        CTC clearance
    		 53 48 101
    PFS
    PFS was calculated as the time interval from randomization until progressive disease (PD), and patients without known progression were censored at the last date they had a documented tumor staging without evidence of progressive disease. Because of incomplete documentation of tumor staging, PFS data were not available for all patients.
    Units: month
        median (full range (min-max))
    		 7.2 (0 to 9.4) 4.1 (2.2 to 5.9) -
    Survival according to randomization arm
    Units: month
        median (full range (min-max))
    		 23.2 (14 to 32.3) 9.1 (8.3 to 9.9) -
    Subject analysis sets

    Subject analysis set title
    Randomized ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib).

    Subject analysis sets values
    		 Randomized ITT population
    Number of subjects
    101
    Age categorical
    total iTT population n = 101 median age 59 (26-80)
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    101
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (standard deviation)
    59 ( 0 )
    Gender categorical
    Units: Subjects
        Female
    101
        Male
    0
    CTC clearence rate (at the time of first CTC assessment and survival)
    CTC clearance rates at the time of first CTC assessment and survival
    Units: Subjects
        CTC clearance
    101
    CTC clearance rate (after study treatment and survival)
    Units: Subjects
        CTC clearance
    101
    PFS
    PFS was calculated as the time interval from randomization until progressive disease (PD), and patients without known progression were censored at the last date they had a documented tumor staging without evidence of progressive disease. Because of incomplete documentation of tumor staging, PFS data were not available for all patients.
    Units: month
        median (full range (min-max))
    4.6 (0 to 22)
    Survival according to randomization arm
    Units: month
        median (full range (min-max))
    21.1 (0 to 21.1)

    End points

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    End points reporting groups
    Reporting group title
    Standard Therapy plus Lapatinib
    Reporting group description
    		 Lapatinib was administered to patients randomized to a treatment with lapatinib in addition to a standard chemo (docetaxel, paclitaxel, capecitabine, vinorelbine, NPLD) - or endocrine therapy (aromatase inhibitor Exemestan, letrozol, anastrozol).

    Reporting group title
    Standard therapy
    Reporting group description
    		 During the randomized treatment period all patients received a standard chemo- or endocrine therapy whether they were allocated to lapatinib treatment or not

    Subject analysis set title
    Randomized ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib).

    Primary: CTC clearance rates at the time of first CTC assessment

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    End point title
    		 CTC clearance rates at the time of first CTC assessment
    End point description
    A first follow-up CTC assessment could be performed in 69 patients (30 and 39 patients in the standard and lapatinib arms, respectively) after a median time of 73 days (interquartile range 64–87 days, range 22–215 days). CTC clearance was observed in 8 (26.7%, 95% CI 10.8% - 42.5%) patients in the standard arm and in 12 (30.8%, 95% CI 16.3% - 45.3%) patients in the lapatinib arm; the difference was not statistically significant (p = 0.710;
    End point type
    Primary
    End point timeframe
    CTC clearance rates at the time of first CTC assessment
    End point values
    		 Standard Therapy plus Lapatinib Standard therapy
    Number of subjects analysed
    12
    8
    Units: %
        median (confidence interval 95%)
    30.8 (16.3 to 45.3)
    26.7 (10.8 to 42.5)
    Attachments
    		 ctc clearance rate after first asessment
    Statistical analysis title
    		 non-parametric
    Comparison groups
    Standard Therapy plus Lapatinib v Standard therapy
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.71
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval

    Primary: CTC clearance rates after study treatment

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    End point title
    		 CTC clearance rates after study treatment
    End point description
    The primary endpoint, i.e., the CTC clearance rate, was calculated as the proportion of patients with at least one CTC detected in 7.5 ml of peripheral blood drawn before treatment that showed no evidence of CTCs in the blood after study treatment (i.e., at the time of the closure visit, which took place either after a patient had received one year of study treatment or at the time the study treatment had to be stopped because of progress, toxicity or patient wish).
    End point type
    Primary
    End point timeframe
    A first follow-up CTC assessment after study treatment
    End point values
    		 Standard Therapy plus Lapatinib Standard therapy
    Number of subjects analysed
    27
    22
    Units: %
        median (confidence interval 95%)
    14.8 (1.4 to 28.2)
    31.8 (12.4 to 51.3)
    Attachments
    		 ctc clearance rate after study treatment
    Statistical analysis title
    		 non-parametric
    Comparison groups
    Standard Therapy plus Lapatinib v Standard therapy
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.156 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - The primary endpoint CTC clearance rate will be evaluated using non-parametric statistical methods appropriate for the analysis of frequencies and rates (i.e. Chi-square tests and modifications thereof). The proportion of pa-tients that show no evidence of CTCs in the blood after the study treatment will be compared between the two treatment arms, and relative risks, odds ratios and their 95% confidence intervals will be reported.
    [2] - All p values will be two-sided if not stated otherwise. The statistical methods described in this section are suited for the data and distributions usually expected in this type of trials. The suitability will be checked after data entry. If necessar

    Secondary: OS

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    End point title
    		 OS
    End point description
    Patients with no evidence of CTCs at the first follow-up CTC assessment (i.e., patients with CTC clearance at the first follow-up) showed better OS than patients with CTCs (CTC clearance: median OS 42.4 months; no CTC clearance: median OS 14.1 months; HR 0.34; 95% CI 0.16–0.70; p = 0.004; Figure 5). Patients showing CTC clearance at the first follow-up CTC assessment also had numerically longer PFS, but the difference was not significant (CTC clearance: median PFS 10.1 months; no CTC clearance: median PFS 6.2 months; HR 0.56; 95% CI 0.29–1.07; p = 0.078).
    End point type
    Secondary
    End point timeframe
    overall survival according to CTC clearance at the time of first follow-up CTC assessment.
    End point values
    		 Randomized ITT population
    Number of subjects analysed
    69
    Units: month
    median (confidence interval 95%)
        ctc clearance
    42.4 (0 to 42.4)
        no ctc clearance
    14.1 (0 to 14.1)
    Attachments
    		 Untitled (Filename: overal survival OS-CTC clearance.pptx)
    No statistical analyses for this end point

    Secondary: PFS

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    End point title
    		 PFS
    End point description
    progression-free survival according to randomization arm
    End point type
    Secondary
    End point timeframe
    progression-free survival according to randomization arm
    End point values
    		 Standard Therapy plus Lapatinib Standard therapy
    Number of subjects analysed
    47
    40
    Units: month
        median (confidence interval 95%)
    7.2 (5.0 to 9.4)
    4.1 (2.2 to 5.9)
    Attachments
    		 PFS randomization arm
    Statistical analysis title
    		 PFS
    Comparison groups
    Standard Therapy plus Lapatinib v Standard therapy
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.092
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.07
    Variability estimate
    Standard deviation
    Notes
    [3] - PFS data were available for 87 patients. The median PFS follow-up time for patients without progression was 4.6 months. Progressive disease occurred in 34 of 40 patients in the standard arm and in 36 of 47 patients in the lapatinib arm. Patients in the lapatinib arm showed a numerically but not significantly better PFS than patients in the standard arm

    Secondary: OS according to randomization

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    End point title
    		 OS according to randomization
    End point description
    Survival according to randomization arm
    End point type
    Secondary
    End point timeframe
    End of study
    End point values
    		 Standard Therapy plus Lapatinib Standard therapy
    Number of subjects analysed
    53
    48
    Units: month
        median (confidence interval 95%)
    23.2 (14 to 32.3)
    9.1 (8.3 to 9.9)
    Attachments
    		 OS randomization arm
    Statistical analysis title
    		 OS randomization arm
    Comparison groups
    Standard Therapy plus Lapatinib v Standard therapy
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.008 [4]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [4] - This was evident based on univariable Cox regression analysis (HR 0.53; 95% CI 0.33–0.84; p = 0.008) and multivariable Cox regression analysis adjusted for the metastasis-free interval (<12 months, >12 months), type of metastases (visceral, non-visce

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    start of study - first dose of study treatment until end of study
    Adverse event reporting additional description
    The safety evaluation was performed in the Safety Population, defined as all randomized patients who received at least one dose of the respective study treatment (chemotherapy or endocrine therapy alone; chemotherapy or endocrine therapy + lapatinib). The safety set comprised 101 patients (48 patients in the standard arm, 53 patients in the lapatin
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Standard arm
    Reporting group description
    		 In conclusion, types and frequencies of adverse events observed in the DETECT III study were as expected for the treatments given in this study, with diarrhea in the lapatinib arm being the most common side effect observed.

    Reporting group title
    Lapatinib arm
    Reporting group description
    		 -

    Serious adverse events
    		 Standard arm Lapatinib arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 48 (43.75%)
    36 / 53 (67.92%)
         number of deaths (all causes)
    40
    33
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Dyspnoea
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anemia
         subjects affected / exposed
    10 / 48 (20.83%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 53 (9.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Leukopenia
         subjects affected / exposed
    5 / 48 (10.42%)
    6 / 53 (11.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    diarrhea
         subjects affected / exposed
    0 / 48 (0.00%)
    13 / 53 (24.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard arm Lapatinib arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 48 (66.67%)
    53 / 53 (100.00%)
    Blood and lymphatic system disorders
    anemia
         subjects affected / exposed
    23 / 48 (47.92%)
    15 / 53 (28.30%)
         occurrences all number
    0
    0
    Leukopenia
         subjects affected / exposed
    7 / 48 (14.58%)
    11 / 53 (20.75%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 48 (39.58%)
    22 / 53 (41.51%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    diarrhea
         subjects affected / exposed
    10 / 48 (20.83%)
    38 / 53 (71.70%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2012
    Change of sponsor from University Hospital Düsseldorf to University Hospital Ulm
    30 Sep 2014
    Subsequent changes in protocol
    09 Jun 2015
    Administrative changes in the protocol
    16 Mar 2016
    Acknowledgement of administrative changes in the trial protocol and patient information

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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
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