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    Clinical Trial Results:
    An open-label, two-stage Phase I/IIa dose escalation study of BT062 in metastatic triple receptor-negative breast cancer and in metastatic transitional cell carcinoma of the urinary bladder

    Summary
    EudraCT number
    2013-003252-20
    Trial protocol
    DE   BE  
    Global end of trial date
    05 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Oct 2021
    First version publication date
    08 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    989
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biotest AG
    Sponsor organisation address
    Landsteinerstr. 5, Dreieich, Germany, 63303
    Public contact
    Dr. Iris Bobenhausen, Biotest AG, iris.bobenhausen@biotest.com
    Scientific contact
    Dr. Iris Bobenhausen, Biotest AG, iris.bobenhausen@biotest.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
    05 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I Part (Dose Escalation):To determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and the recommended Phase II dose (RPTD) of BT062 in patients with metastatic triple-negative breast cancer (TNBC) or metastatic transitional cell carcinoma of the urinary bladder ((TCCUB). Phase IIa Part (Cohort Expansion):To assess the proportion of patients experiencing disease control (SD, PR or CR) according to RECIST criteria during the first 3 treatment cycles.
    Protection of trial subjects
    Patients who experience progression disease (PD) are not eligible for further treatment cycles and will complete the study according to the protocol. If a patient experiences a DLT, the study treatment must be stopped in this particular patient. In case of toxicity other than DLT, the Investigator will decide whether the patient is eligible for further treatment cycles. No patient will receive more than 3 doses of BT062 during a 28-day treatment cycle. Patients initially treated at a dose level higher than the finally defined RPTD, and who did not experience unacceptable toxicity or PD, may continue treatment at this dose level or below unless unacceptable BT062-related toxicity or PD is detected. A dose of BT062 higher than the MAD will never be permitted to be administered. A DLT is always considered as an AE. For safety monitoring, physical examinations, vital signs, ECG, pregnancy test, Fecal Occult Blood and safety laboratory parameters and Eastern Cooperative Oncology Group Performance Status. Any unfavorable or unintended sign, symptom, or disease that appears or worsens in a study subject during the period of observation in a clinical study were reported as an AE.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    8 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Germany: 19
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    25
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment period: 11-Mar-2014 to 15-Jul-2016 (27 months) Countries: Belgium and Germany Subjects with metastatic TNBC (stage IV) with histochemical confirmation of the absence (<1%) of progesterone receptors, estrogen receptors, and human epidermal growth factor receptors or with metastatic TCCUB (stage IV).

    Pre-assignment
    Screening details
    • Subject aged ≥18 with relapsed and/or refractory disease at a stage that could not be controlled adequately by surgery, radiotherapy, or standard chemotherapy. • Measurable disease acc. to RECIST v1.1 with at least 1 measurable lesion and at least 1 tumor biopsy with histologically confirmed. • Estimated life expectancy ≥ 12 weeks and ECOG≤2.

    Period 1
    Period 1 title
    Phase I
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    100 mg/m2
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    BT062 100 mg / m² BSA
    Investigational medicinal product code
    Other name
    Indatuximab ravtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT062 has been provided as a pre-filled, single-use vial containing 25 mg BT062 in 5 mL solution (5 mg / mL). The dose was calculated as mg / m2 BSA. BT062 will be administered intravenously at Days 1, 8 and 15 during a 28-day treatment cycle.

    Arm title
    120 mg / m²
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    BT062 120 mg / m² BSA
    Investigational medicinal product code
    Other name
    Indatuximab ravtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT062 has been provided as a pre-filled, single-use vial containing 25 mg BT062 in 5 mL solution (5 mg / mL). The dose was calculated as mg / m2 BSA. BT062 will be administered intravenously at Days 1, 8 and 15 during a 28-day treatment cycle.

    Arm title
    140 mg/m2
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    BT062 140 mg / m² BSA
    Investigational medicinal product code
    Other name
    Indatuximab ravtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT062 has been provided as a pre-filled, single-use vial containing 25 mg BT062 in 5 mL solution (5 mg / mL). The dose was calculated as mg / m2 BSA. BT062 will be administered intravenously at Days 1, 8 and 15 during a 28-day treatment cycle.

    Number of subjects in period 1 [1]
    100 mg/m2 120 mg / m² 140 mg/m2
    Started
    6
    4
    4
    Completed
    5
    3
    3
    Not completed
    1
    1
    1
         no post dose safety/RECIST assessment
    1
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 20 subjects screened for Phase I, 14 subjects received at least 1 of 3 dose levels (100, 120, or 140 mg/m2) of BT062. 6 screened subjects were screen failures. 6 subjects continued Phase IIa 36 subjects were directly screened for Phase IIa. Therefore in total 56 subjects were screened in this trial.
    Period 2
    Period 2 title
    Phase IIa
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    TNBC
    Arm description
    subjects with triple-negative breast cancer
    Arm type
    Experimental

    Investigational medicinal product name
    BT062 100 mg / m² BSA
    Investigational medicinal product code
    Other name
    Indatuximab ravtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT062 has been provided as a pre-filled, single-use vial containing 25 mg BT062 in 5 mL solution (5 mg / mL). The dose was calculated as mg / m2 BSA. BT062 will be administered intravenously at Days 1, 8 and 15 during a 28-day treatment cycle.

    Arm title
    TCCUB
    Arm description
    Subjects with transitional cell cancer of the urinary bladder
    Arm type
    Experimental

    Investigational medicinal product name
    BT062 100 mg / m² BSA
    Investigational medicinal product code
    Other name
    Indatuximab ravtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BT062 has been provided as a pre-filled, single-use vial containing 25 mg BT062 in 5 mL solution (5 mg / mL). The dose was calculated as mg / m2 BSA. BT062 will be administered intravenously at Days 1, 8 and 15 during a 28-day treatment cycle.

    Number of subjects in period 2
    TNBC TCCUB
    Started
    15
    16
    Completed
    13
    14
    Not completed
    2
    2
         no post dose safety/RECIST assessment
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    100 mg/m2
    Reporting group description
    -

    Reporting group title
    120 mg / m²
    Reporting group description
    -

    Reporting group title
    140 mg/m2
    Reporting group description
    -

    Reporting group values
    100 mg/m2 120 mg / m² 140 mg/m2 Total
    Number of subjects
    6 4 4 14
    Age categorical
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.3 ( 11.5 ) 54.8 ( 7.63 ) 67.5 ( 5.45 ) -
    Gender categorical
    Units: Subjects
        Female
    2 4 3 9
        Male
    4 0 1 5
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population will include all patients who were administered at least 1 dose of study medication. The safety population will be used for all analyses of safety endpoints. The safety population will be used for the presentation of patients in all patient listings (except disposition).

    Subject analysis set title
    ENROLLED POPULATION
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The enrolled population will include all patients enrolled. Enrolled is defined as informed consent given. Unless specified otherwise, this enrolled population will be used for listings and summaries of patient disposition. Here as a workaround enrolled population entered is number of patients randomized to avoid errors.

    Subject analysis set title
    INTENTION-TO-TREAT POPULATION
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population (both phases) will include all patients enrolled, who have received at least one dose of BT062, have both a post-dose safety assessment, e.g. AE, vital sign and a post-dose RECIST assessment.

    Subject analysis set title
    PER PROTOCOL POPULATION
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (PP) will include patients from the ITT population who have completed the study without major protocol deviation.

    Subject analysis set title
    PHARMACOKINETIC POPULATION
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population is defined as all patients who received any amount of study medication and who had at least one measurement of BT062 or derivative component of BT062 in plasma or urine.

    Subject analysis sets values
    Safety Population ENROLLED POPULATION INTENTION-TO-TREAT POPULATION PER PROTOCOL POPULATION PHARMACOKINETIC POPULATION
    Number of subjects
    39
    39
    33
    28
    38
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.3 ( 13.85 )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    24
        Male
    15

    End points

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    End points reporting groups
    Reporting group title
    100 mg/m2
    Reporting group description
    -

    Reporting group title
    120 mg / m²
    Reporting group description
    -

    Reporting group title
    140 mg/m2
    Reporting group description
    -
    Reporting group title
    TNBC
    Reporting group description
    subjects with triple-negative breast cancer

    Reporting group title
    TCCUB
    Reporting group description
    Subjects with transitional cell cancer of the urinary bladder

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population will include all patients who were administered at least 1 dose of study medication. The safety population will be used for all analyses of safety endpoints. The safety population will be used for the presentation of patients in all patient listings (except disposition).

    Subject analysis set title
    ENROLLED POPULATION
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The enrolled population will include all patients enrolled. Enrolled is defined as informed consent given. Unless specified otherwise, this enrolled population will be used for listings and summaries of patient disposition. Here as a workaround enrolled population entered is number of patients randomized to avoid errors.

    Subject analysis set title
    INTENTION-TO-TREAT POPULATION
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) population (both phases) will include all patients enrolled, who have received at least one dose of BT062, have both a post-dose safety assessment, e.g. AE, vital sign and a post-dose RECIST assessment.

    Subject analysis set title
    PER PROTOCOL POPULATION
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (PP) will include patients from the ITT population who have completed the study without major protocol deviation.

    Subject analysis set title
    PHARMACOKINETIC POPULATION
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population is defined as all patients who received any amount of study medication and who had at least one measurement of BT062 or derivative component of BT062 in plasma or urine.

    Primary: Proportion of disease control (SD, PR, or CR) during the first 3 treatment cycles

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    End point title
    Proportion of disease control (SD, PR, or CR) during the first 3 treatment cycles [1]
    End point description
    The primary efficacy endpoint in Phase IIa is the proportion of patients experiencing disease control (stable disease, partial response, or complete response) defined by Response Criteria in Solid Tumors (RECIST) v1.1 criteria for each tumor entity during the first 3 treatment cycles.
    End point type
    Primary
    End point timeframe
    during the first 3 treatment cycles ( up to 3 months)
    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: Categorical variables will be summarized using number of observations (n), frequency, and percentages of patients, unless stated otherwise. Unless stated otherwise, the calculation of percentages will be based on the total number of patients in the population of interest.
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 TNBC TCCUB INTENTION-TO-TREAT POPULATION
    Number of subjects analysed
    5
    3
    3
    13
    14
    33
    Units: subjects
        Disease Control - Yes
    0
    1
    1
    3
    4
    9
        Disease Control - No
    5
    2
    2
    10
    10
    24
    No statistical analyses for this end point

    Primary: Dose-Limiting Toxicities

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    End point title
    Dose-Limiting Toxicities [2]
    End point description
    The primary objective of the phase I part is to determine the dose-limiting toxicities (DLTs). A DLT is always considered as an AE. The following criteria should be checked: 1. SAE or AE of severity Grade 3 or higher, which is related to BT062. 2. The following AEs will be considered as DLTs, if pre-specified criteria are fulfilled: • Grade 3-4 nausea and vomiting, if lasting longer than 3 days despite optimal antiemetic medication; • Grade 3-4 diarrhea, if lasting longer than 3 days despite optimal antidiarrheal medication; • Grade 4 neutropenia, if lasting longer than 7 days; • Grade 3-4 neutropenia*, if the body core temperature is higher than or equal 38.3°C; • Grade 3 thrombocytopenia*, if platelet count is < 30,000 / μL • Grade 3 thrombocytopenia, if associated with clinically significant bleeding • Grade 4 thrombocytopenia.
    End point type
    Primary
    End point timeframe
    From Baseline to the end of Phase I
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Categorical variables will be summarized using number of observations (n), frequency, and percentages of patients, unless stated otherwise. Unless stated otherwise, the calculation of percentages will be based on the total number of patients in the population of interest.
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 Safety Population
    Number of subjects analysed
    6
    4
    4
    14
    Units: subjects
        Subject with at least 1 DLT
    0
    2
    1
    4
        Skin and Subcutaneous Tissue Disorders
    0
    2
    1
    3
        Dermatitis Exfoliative
    0
    1
    0
    1
        Palmar-Plantar Erythrodysaesthesia Syndrome
    0
    0
    0
    1
        Rash
    0
    0
    1
    0
        Rash Maculo-Papular
    0
    1
    0
    1
        Gastrointestinal Disorders
    0
    0
    0
    1
        Stomatitis
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Overall Lesion Response Defined by RECIST v1.1

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    End point title
    Overall Lesion Response Defined by RECIST v1.1
    End point description
    A patient will be counted only once for their best overall lesion response. The order from best to worse is Complete Response (CR) >Partial Response (PR)>Stable disease (SD)>Progression disease (PD)>NE ( NE = Not Evaluable).
    End point type
    Secondary
    End point timeframe
    from baseline to end of study
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 TNBC TCCUB INTENTION-TO-TREAT POPULATION
    Number of subjects analysed
    5
    3
    3
    13
    14
    33
    Units: subjects
        CR
    0
    0
    0
    0
    0
    0
        PR
    0
    1
    0
    1
    1
    3
        SD
    0
    0
    1
    2
    3
    6
        PD
    5
    2
    2
    10
    10
    24
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    Progression free survival
    End point description
    Progression free survival is defined as the duration from start of the treatment to disease progression or death (regardless of cause of death), whichever is earlier. If the patient does not have a documented date of progression or death, PFS will be censored at the date of the last adequate assessment. PFS (weeks) = ([Date of progression / death – date of first dose] + 1) / 7 PFS will be analyzed using Kaplan Meier quartile estimates along with 2-sided 95% CIs.
    End point type
    Secondary
    End point timeframe
    From Baseline to the end of study
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 TNBC TCCUB INTENTION-TO-TREAT POPULATION
    Number of subjects analysed
    5
    3
    3
    13
    14
    33
    Units: Week
        median (confidence interval 95%)
    10.1 (5.3 to 13.3)
    9.9 (7.1 to 13.6)
    10.7 (9.1 to 14.4)
    8.0 (5.1 to 12.7)
    11.6 (8.0 to 31.9)
    10.7 (8.0 to 12.1)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival (OS) is defined as the time from the start of the treatment to death from any cause. If the patient does not have a documented date of death, OS will be censored at the date of the patient was last known to be alive. OS (weeks) = ([Date of death – date of first dose] + 1) / 7 OS will be analyzed using Kaplan Meier quartile estimates along with 2-sided 95% CIs. For Reporting Group 2 the upper limit of the Confidence Interval 95% is non-estimable. Therefore the longest overall survival was entered to avoid errors. The longest overall survival reported was 110.6 weeks. The subject was still alive after 110.6 weeks at study end.
    End point type
    Secondary
    End point timeframe
    From Baseline to the end of study
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 TNBC TCCUB INTENTION-TO-TREAT POPULATION
    Number of subjects analysed
    5
    3
    3
    13
    14
    33
    Units: week
        median (confidence interval 95%)
    26.9 (16.3 to 50.7)
    32.6 (28.6 to 110.6)
    40.9 (31.9 to 52.6)
    24.1 (12.0 to 44.9)
    28.6 (18.3 to 50.7)
    31.9 (24.1 to 42.4)
    No statistical analyses for this end point

    Secondary: Duration of Stable Disease

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    End point title
    Duration of Stable Disease
    End point description
    Duration of stable disease will be assessed following the RECIST v1.1 criteria. The DSD is measured from the start of the treatment until the criteria for progression are met, or until death of the patient from any cause. Stable disease will therefore be assumed from the start of treatment until the criteria for disease progression are first met. If the patient does not have a documented date of progression or death, DSD will be censored at the date of the last adequate assessment. DSD (weeks) = ([Date of progression/death {where cause is not PD} – date of first dose] + 1) / 7 DSD has been presented as a swimmer plot with DSD on the Y axis and patient number on the X axis. No summary data is available for this end point. In the attached figure, all subject numbers were deleted due to data privacy protection. The best result (longest duration of stable disease) was entered in the corresponding result value field).
    End point type
    Secondary
    End point timeframe
    From Baseline to the end of study
    End point values
    100 mg/m2 120 mg / m² 140 mg/m2 TNBC TCCUB INTENTION-TO-TREAT POPULATION
    Number of subjects analysed
    5
    3
    3
    13
    14
    33
    Units: week
        number (not applicable)
    13.3
    13.6
    14.4
    27.3
    60
    60
    Attachments
    Duration of stable disease of individual subjects
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were documented after written consent has been obtained until patient's exit from the study.
    Adverse event reporting additional description
    Non-treatment emergent AEs (after written consent has been obtained, but before the first dose of study drug started), and not related AEs after patient's Exit from the study were not considered here.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    The safety population included all enrolled subjects who were administered at least 1 dose of BT062.

    Serious adverse events
    Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 39 (48.72%)
         number of deaths (all causes)
    9
         number of deaths resulting from adverse events
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Electrocardiogram QT prolonged
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
    Additional description: Fatal outcome, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Disease progression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Infusion site extravasation
    Additional description: Resolving, no Action with study drug, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Stomatitis
    Additional description: Resolving, drug withdrawn, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
    Additional description: Fatal outcome, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intestinal obstruction
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative
    Additional description: Resolving, dose reduction, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
    Additional description: Resolving, study drug temporarily stopped, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
    Additional description: Resolving, dose reduced, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Disorientation
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Musculoskeletal and connective tissue disorders
    Soft tissue necrosis
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
    Additional description: Resolving, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
    Additional description: Resolved, not related to study medication.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile infection
    Additional description: Resolved, not related.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
    Additional description: Resolved, not related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site cellulitis
    Additional description: Resolving, study drug temporarily interrupted, related to study drug.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
    Additional description: Not resolved, , not related to study drug, subject died 4 days later due to gastrointestinal haemorrhage.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    9
    Hypotension
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 39 (53.85%)
         occurrences all number
    40
    Oedema peripheral
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    15
    Pyrexia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Chills
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Feeling cold
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Mucosal inflammation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    26
    Cough
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    8
    Pleural effusion
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    8
    Rhinorrhoea
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Anxiety
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Sleep disorder
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Confusional state
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    13
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    9
    Weight decreased
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    5
    Blood creatinine increased
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    10
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Glomerular filtration rate decreased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    5
    Lipase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    7
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    7
    Dizziness
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Dysgeusia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Polyneuropathy
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    7
    Dysaesthesia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    20
    Lymphadenopathy
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 39 (51.28%)
         occurrences all number
    33
    Nausea
         subjects affected / exposed
    14 / 39 (35.90%)
         occurrences all number
    20
    Constipation
         subjects affected / exposed
    11 / 39 (28.21%)
         occurrences all number
    16
    Stomatitis
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    11
    Vomiting
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    10
    Abdominal pain upper
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    6
    Dry mouth
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    6
    Dyspepsia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastrointestinal motility disorder
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    9
    Pruritus
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    7
    Rash
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    16
    Rash maculo-papular
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    8
    Dermatitis bullous
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Night sweats
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Skin ulcer
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Dysuria
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Haematuria
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    5
    Pollakiuria
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Urinary incontinence
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    10
    Muscle spasms
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    8
    Arthralgia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Cystitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Bronchitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Skin infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 39 (30.77%)
         occurrences all number
    20
    Hypokalaemia
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    20
    Dehydration
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    9
    Hypomagnesaemia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Hypophosphataemia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    15
    Hypocalcaemia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    6
    Hyperglycaemia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Hyponatraemia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    8
    Hyperuricaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2013
    Protocol amendment 1 dated 05-DEC-2013 introduced the following changes: •The recruitment timeline and assumed duration of the study were adapted. • The FACT GOG-Ntx questionnaire was added. • Minor clarifications to the flowchart were made. • The DLT definition of thrombocytopenia was re-worded to make it clearer without changing the criteria. • More emphasis was put on the recommendation to conduct further unscheduled visits if AEs were still ongoing at study end. • The number of cases with SAEs and the cut-off date to determine this number of cases in the benefit-risk evaluation section of the protocol (Section 12.5.2) were updated, on the basis of data updates from other ongoing studies with BT062. • The option to have CD138 assessed on historic biopsies, while a fresh biopsy still remained mandatory, was added. • Wording saying CA 15-3 and carcinoembryonic antigen (CEA) levels in breast cancer patients were to be assessed at baseline in addition to screening was removed to correct a discrepancy with the flow chart. • The description on optimal biomarker time points was corrected to match the flowchart. • It was further clarified that biological samples to be used for PK analysis consisted of sodium heparin plasma samples. • Blood gas analyses were removed from the clinical chemistry panel as it had been included in error. • A reminder on the limitations of the Cockcroft-Gault equation in showing the true glomerular filtration rate was included. • It was further clarified in the statistical section of the protocol that further recruitment was to be stopped if insufficient efficacy was found. The term ‘disease control or better’ was corrected into ‘disease control’ because disease control also included the best possible outcome CR.
    11 Mar 2015
    The major changes: • Estimated end dates of enrollment and data cut-off were updated. • Enrollment of subjects who were scheduled to continue an ongoing denosumab treatment as concomitant medication during treatment with BT062 was permitted under certain restrictions and denosumab PK-specific time points were added to the description of the study visits. • Collection of denosumab PK samples and instructions for administering BT062 and denosumab as co-medication were added. In addition, all screening results had to be completed before the first dose of BT062 and it was explained that informed consent and biopsy collection could take place even before screening period. • In breast cancer subjects who failed more than 2 treatment regimens, the requirement to be eligible for the current study was that no PD was observed earlier than 9 weeks of the start of the last unsuccessful treatment. Treatments of a short duration < 9weeks due to insufficient tolerability or other reasons, with absence of disease progression did not have to lead to exclusion of a subject. • In case participation ended for a reason other than PD and the subject had received at least 2 cycles of BT062, the first tumor staging data from routine diagnostics after discontinuation were to be captured in the eCRF. • Previous chemotherapies, including adjuvant therapies, sequential regimens, and in-situ therapies were provided. • Guidance on the timing of written informed consent was provided. • Guidance on the timing of the 30-day follow-up depending on the reason of study discontinuation was provided. • A brief description of extravasation as a potential source of risk or discomfort was added. • A more detailed description of molecular parameters related to PK was added to clarify the aim to also analyze potential BT062 metabolites. • suspicion of a technical complaint or product complaint in a Biotest product which caused an infection in a subject, represented an IRAE.
    02 Jun 2016
    Protocol amendment 3, dated 02-JUN-2016 introduced the following changes: • It was clarified that disease control observation was done during the first 3 cycles. • The ITT population and subsequently also the subject replacement section were adapted according to RECIST criteria. Every subject treated with BT062 who had 1 post-treatment tumor staging or DLT/intolerabilities was to be included in the ITT population. Subjects, who discontinued the treatment before the first post-dose tumor staging and for whom no DLT or other sign of insufficient tolerability was observed, needed to be replaced. In case of SD, the minimum time interval between baseline tumor staging and first post-dose tumor staging was defined as 6 weeks. • It was clarified that tumor staging was planned after every third treatment cycle, but could be performed at any time during the study, if clinically indicated. • The number of PK parameters analyzed was reduced for Phase I of the study. • Certain other sections were amended for clarification.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Jul 2016
    Recruitment was stopped prematurely during Stage 1 of Phase IIa because of a low recruitment rate, an unacceptably large number of subjects prematurely terminating the study, and limited monotherapeutic efficacy in these indications with end-stage patients and exhausted treatment options.
    -

    Limitations and caveats

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