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    Clinical Trial Results:
    A randomized, double-blind, parallel group, Phase III trial to compare the efficacy, safety, and immunogenicity of TX05 with Herceptin in subjects with HER2 positive early breast cancer

    Summary
    EudraCT number
    		 2017-004190-13
    Trial protocol
    		 HU   BG  
    Global end of trial date
    27 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Apr 2022
    First version publication date
    02 Apr 2022
    Other versions
    Summary report(s)
    		 TX05-03 Results Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    TX05-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03556358
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tanvex Biologics Corp.
    Sponsor organisation address
    2030 Main Street, Suite 1050, Irvine, United States, CA 96214
    Public contact
    Jennifer Lai, Tanvex Biologics Corp., +1 949 483 8507, jennifer.lai@tanvex.com
    Scientific contact
    Jennifer Lai, Tanvex Biologics Corp., +1 949 483 8507, jennifer.lai@tanvex.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the therapeutic equivalence of TX05 (proposed biosimilar trastuzumab) to Herceptin (trastuzumab) based on the pathologic complete response (pCR) rate following neoadjuvant chemotherapy, defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0), in subjects with human epidermal growth factor receptor positive (HER2+) invasive early breast cancer (EBC).
    Protection of trial subjects
    This study was conducted in accordance with the provisions of the Declaration of Helsinki (October 1996) and all revisions thereof, and in accordance with Food and Drug Administration regulations (Code of Federal Regulations, Sections 312.50 and 312.56) and with International Council for Harmonization guidelines on Good Clinical Practice (CPMP 135/95) and with applicable regulatory requirements. Protection of subject personal data was ensured by not including subject names on any Sponsor forms, reports, publications, or in any other disclosures, except where required by laws. The nature and purpose of the study were fully explained to each subject (or their legally responsible guardian). The informed consent form (ICF) was explained to the subjects prior to any study procedures being performed. Each subject signed an ICF containing appropriate study and study drug information and was provided a copy of the ICF. Appropriate study restrictions, based on the risks and discomforts anticipated to be associated with TX05 in subjects with breast cancer, were implemented including screening procedures and exclusion criteria to ensure the safety of subjects.
    Background therapy
    		 This was a randomised, double-blinded, parallel group, equivalence, multicenter Phase III study. The study contained 8 cycles of neoadjuvant treatment and the subjects were randomized into two groups, TX05 group and Herceptin group. For Cycles 1 to 4, the subjects in both the groups received intravenous (IV) epirubicin (75 mg/m^2) and cyclophosphamide (600 mg/m^2) every 3 weeks. During Cycles 5 to 8, the subjects in the TX05 received IV TX05 (8 mg/kg loading dose then 6 mg/kg) and paclitaxel (175 mg/m^2) every 3 weeks, and the subjects in the Herceptin group were to receive IV Herceptin (8 mg/kg loading dose then 6 mg/kg) and paclitaxel (175 mg/m^2) every 3 weeks.
    Evidence for comparator
    		 Herceptin was approved for marketing in the US in 1998 and in the EU in 2000.It is indicated for the treatment of HER2-overexpressing breast cancer.
    Actual start date of recruitment
    28 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Belarus: 38
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Georgia: 34
    Country: Number of subjects enrolled
    India: 93
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Peru: 87
    Country: Number of subjects enrolled
    Philippines: 37
    Country: Number of subjects enrolled
    Russian Federation: 327
    Country: Number of subjects enrolled
    Ukraine: 136
    Worldwide total number of subjects
    809
    EEA total number of subjects
    8
    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)
    671
    From 65 to 84 years
    137
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligibility criteria - Signed written informed consent. Females ≥ 18 years of age. Planned surgical resection of breast tumor (lumpectomy or mastectomy, and SN biopsy or ALND). Planned neoadjuvant chemotherapy. Histologically confirmed HER2 overexpressing invasive primary operable Stage II/IIIa breast cancer.

    Pre-assignment
    Screening details
    		 CT scan of chest or MRI of chest (only if CT scan could not be performed) and bilateral mammography or ultrasound of the breast were required at Screening for all subjects. Subjects of childbearing potential were to have a blood serum pregnancy test at Screening. Physical examinations were conducted at Screening.

    Pre-assignment period milestones
    Number of subjects started
    		 809
    Number of subjects completed
    		 806

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Period 1
    Period 1 title
    Treatment Period 1, Cycle 1 to Cycle 4
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TX05
    Arm description
    		 Epirubicin 75 mg/m2 intravenous bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV infusion, on Day 1 of Cycle 1 and thereafter 3 weeks until Cycle 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) epirubicin, 75 mg/m2 every 3 weeks for 4 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles

    Arm title
    		 Herceptin
    Arm description
    		 Epirubicin 75 mg/m2 intravenous bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV infusion, on Day 1 of Cycle 1 and thereafter 3 weeks until Cycle 4
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) epirubicin, 75 mg/m2 every 3 weeks for 4 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    cyclophosphamide 600 mg/m2 every 3 weeks for 4 Cycles.

    Number of subjects in period 1 [1]
    		TX05 Herceptin
    Started
    401
    405
    Completed
    394
    400
    Not completed
    7
    5
         Consent withdrawn by subject
    5
    -
         Adverse event, non-fatal
    -
    2
         Covid-19
    1
    1
         Decision of medical monitor
    -
    1
         Progressive disease
    1
    -
         Protocol deviation
    -
    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: 3 patients were randomized, but not treated.
    Period 2
    Period 2 title
    Treatment Period 2, Cycle 5 to Cycle 8
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Both randomization and blinding techniques were used in this study to minimize bias. This was a double-blinded study and so randomized treatment assignments were blinded to the subject, investigator/study staff and Sponsor’s study team conducting the study. The central pathology readers for pCR were also blinded to study treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TX05
    Arm description
    		 TX05 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion (Cycle 5). TX05 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 to 8).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/skin-prick test
    Routes of administration
    Intravenous use
    Dosage and administration details
    TX05 8 mg/kg body weight by 90-minute IV infusion (Cycle 5). TX05 6 mg/kg body weight by 60-minute IV infusion, on Day 1 of the treatment cycle (Cycles 6 to 8).

    Arm title
    		 Herceptin
    Arm description
    		 Herceptin 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion (Cycle 5). Herceptin 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 through 8).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Herceptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/skin-prick test
    Routes of administration
    Intravenous use
    Dosage and administration details
    Herceptin 8 mg/kg body weight by 90-minute IV infusion (Cycle 5). Herceptin 6 mg/kg body weight by 60-minute IV infusion on Day 1 of the treatment cycle (Cycles 6 through 8).

    Number of subjects in period 2
    		TX05 Herceptin
    Started
    394
    400
    Completed
    393
    393
    Not completed
    1
    7
         Adverse event, serious fatal
    -
    1
         Patient decision
    1
    -
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    -
    1
         No information available
    -
    2
         Covid -19
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1, Cycle 1 to Cycle 4
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1, Cycle 1 to Cycle 4 Total
    Number of subjects
    		 806 806
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 662 662
        From 65-84 years
    		 143 143
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 11.29 ) -
    Gender categorical
    Units: Subjects
        Female
    		 806 806
        Male
    		 0 0
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who were randomized into the study and had received at least one dose of study drug (TX05 or Herceptin). The safety population was used for safety and immunogenicity endpoints.

    Subject analysis set title
    mITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population included all subjects who were randomized into the study and received at least 1 dose of TX05 or Herceptin. The mITT population was used for sensitivity analysis of the primary endpoint and for primary analysis of secondary endpoints.

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population included all subjects who met all of the following criteria: Randomized and receive at least one dose of study drug, either TX05 or Herceptin. No major protocol deviations that impacted the efficacy endpoints. An adequate sample from definitive surgical resection of their primary tumor for pathologic evaluation of residual tumor.

    Subject analysis sets values
    		 Safety Population mITT Population Per Protocol Population
    Number of subjects
    794
    794
    674
    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)
    652
    652
        From 65-84 years
    141
    141
        85 years and over
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.8 ( 11.32 )
    53.8 ( 11.32 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    794
    794
    674
        Male
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    TX05
    Reporting group description
    		 Epirubicin 75 mg/m2 intravenous bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV infusion, on Day 1 of Cycle 1 and thereafter 3 weeks until Cycle 4

    Reporting group title
    Herceptin
    Reporting group description
    		 Epirubicin 75 mg/m2 intravenous bolus infusion and cyclophosphamide 600 mg/m2 by 30-minute IV infusion, on Day 1 of Cycle 1 and thereafter 3 weeks until Cycle 4
    Reporting group title
    TX05
    Reporting group description
    		 TX05 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion (Cycle 5). TX05 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 to 8).

    Reporting group title
    Herceptin
    Reporting group description
    		 Herceptin 8 mg/kg body weight by 90-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion (Cycle 5). Herceptin 6 mg/kg body weight by 60-minute IV infusion and paclitaxel 175 mg/m2 administered over 60 minutes by IV infusion, on Day 1 of the treatment cycle (Cycles 6 through 8).

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all subjects who were randomized into the study and had received at least one dose of study drug (TX05 or Herceptin). The safety population was used for safety and immunogenicity endpoints.

    Subject analysis set title
    mITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intent-to-treat (mITT) population included all subjects who were randomized into the study and received at least 1 dose of TX05 or Herceptin. The mITT population was used for sensitivity analysis of the primary endpoint and for primary analysis of secondary endpoints.

    Subject analysis set title
    Per Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population included all subjects who met all of the following criteria: Randomized and receive at least one dose of study drug, either TX05 or Herceptin. No major protocol deviations that impacted the efficacy endpoints. An adequate sample from definitive surgical resection of their primary tumor for pathologic evaluation of residual tumor.

    Primary: Proportion of subjects with a pathologic complete response (pCR) after the neoadjuvant chemotherapy in the per protocol (PP) population based on central lab review

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    End point title
    		 Proportion of subjects with a pathologic complete response (pCR) after the neoadjuvant chemotherapy in the per protocol (PP) population based on central lab review
    End point description
    To demonstrate the therapeutic equivalence of TX05 (proposed biosimilar trastuzumab) to Herceptin (trastuzumab) based on the pathologic complete response (pCR) rate following neoadjuvant chemotherapy, defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (ypT0/Tis ypN0), in subjects with HER2 positive (HER2+) invasive EBC.
    End point type
    Primary
    End point timeframe
    After EOT/ET visit
    End point values
    		 TX05 Herceptin Per Protocol Population
    Number of subjects analysed
    336
    338
    674 [1]
    Units: Number of subjects
    164
    153
    317
    Notes
    [1] - Per protocol
    Statistical analysis title
    		 pCR by Central Pathological Review
    Comparison groups
    TX05 v Herceptin
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    		 Asymptotic method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0783
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9185
         upper limit
    		 1.2659
    Notes
    [2] - The equivalence margin was determined as [0.755, 1.325] to protect 50% of the effect size based on a log scale (upper equivalence limit was exp [0.5 × ln (1.755) =1.325]).

    Primary: Sensitivity analysis: Proportion of subjects with pCR in mITT by central analysis

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    End point title
    		 Sensitivity analysis: Proportion of subjects with pCR in mITT by central analysis
    End point description
    The combined risk ratio for trastuzumab plus chemotherapy over chemotherapy alone was estimated to be 1.755. The equivalence margin was determined as [0.755, 1.325] to protect 50% of the effect size based on a log scale (upper equivalence limit was exp [0.5 x ln (1.755)=1.325])
    End point type
    Primary
    End point timeframe
    After EOT/ET visit
    End point values
    		 TX05 Herceptin mITT Population
    Number of subjects analysed
    394
    400
    794 [3]
    Units: Subjects
    172
    158
    330
    Notes
    [3] - miTT by central analysis
    Statistical analysis title
    		 pCR by Central Pathological Review
    Statistical analysis description
    Sensitivity analysis
    Comparison groups
    TX05 v Herceptin
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9369
         upper limit
    		 1.3037

    Primary: Sensitivity analysis: Proportion of subjects with pCR in mITT by local analysis

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    End point title
    		 Sensitivity analysis: Proportion of subjects with pCR in mITT by local analysis
    End point description
    the combined risk ratio for trastuzumab plus chemotherapy over chemotherapy alone was estimated to be 1.755. The equivalence margin was determined as [0.755, 1.325] to protect 50% of the effect size based on a log scale (upper equivalence limit was exp [0.5 × ln (1.755) =1.325]).
    End point type
    Primary
    End point timeframe
    After EOT/ET visit
    End point values
    		 TX05 Herceptin mITT Population
    Number of subjects analysed
    394
    400
    794 [4]
    Units: Subjects
    190
    176
    366
    Notes
    [4] - miTT by local analysis
    Statistical analysis title
    		 pCR in mITT by local analysis
    Comparison groups
    TX05 v Herceptin
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9427
         upper limit
    		 1.2742

    Primary: Sensitivity analysis: pCR analysis in PP with stratification factors

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    End point title
    		 Sensitivity analysis: pCR analysis in PP with stratification factors
    End point description
    the combined risk ratio for trastuzumab plus chemotherapy over chemotherapy alone was estimated to be 1.755. The equivalence margin was determined as [0.755, 1.325] to protect 50% of the effect size based on a log scale (upper equivalence limit was exp [0.5 × ln (1.755) =1.325]).
    End point type
    Primary
    End point timeframe
    After EOT/ET visit
    End point values
    		 TX05 Herceptin Per Protocol Population
    Number of subjects analysed
    336
    338
    674 [5]
    Units: Subjects
    164
    153
    317
    Notes
    [5] - Per protocol
    Statistical analysis title
    		 pCR analysis in PP with stratification factors
    Comparison groups
    TX05 v Herceptin
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0842
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9283
         upper limit
    		 1.2662

    Secondary: Percentage of subjects with an objective response rate (ORR) after the neoadjuvant chemotherapy in the modified intent-to-treat (mITT) population

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    End point title
    		 Percentage of subjects with an objective response rate (ORR) after the neoadjuvant chemotherapy in the modified intent-to-treat (mITT) population
    End point description
    End point type
    Secondary
    End point timeframe
    EOT/ET visit (at Week 24 )
    End point values
    		 TX05 Herceptin Per Protocol Population
    Number of subjects analysed
    394
    400
    794 [6]
    Units: Subjects
    332
    340
    672
    Notes
    [6] - miTT population
    Statistical analysis title
    		 Subjects with ORR in mITT population
    Comparison groups
    Herceptin v TX05
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9913
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9343
         upper limit
    		 1.0519

    Secondary: Percentage of subjects with positive Anti-drug antibodies (ADA) result in the safety population

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    End point title
    		 Percentage of subjects with positive Anti-drug antibodies (ADA) result in the safety population
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline of Cycle 5 (Week 12), Cycle 7 (Week 18), and EOT/ET (Week 24)
    End point values
    		 TX05 Herceptin Safety Population
    Number of subjects analysed
    347
    348
    695 [7]
    Units: Number of subjects
    4
    12
    16
    Notes
    [7] - Patients who were tested.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with negative ADA result in the safety population

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    End point title
    		 Percentage of subjects with negative ADA result in the safety population
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline of Cycle 5 (Week 12), Cycle 7 (Week 18), and EOT/ET (Week 24)
    End point values
    		 TX05 Herceptin Safety Population
    Number of subjects analysed
    347
    348
    695 [8]
    Units: Number of subjects
    342
    336
    678
    Notes
    [8] - Patients who were tested.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with positive neutralizing antibodies (NAb) result out of ADA positive samples in the safety population

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    End point title
    		 Percentage of subjects with positive neutralizing antibodies (NAb) result out of ADA positive samples in the safety population
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline of Cycle 5 (Week 12), Cycle 7 (Week 18), and EOT/ET (Week 24)
    End point values
    		 TX05 Herceptin Safety Population
    Number of subjects analysed
    347
    348
    695 [9]
    Units: Number of subjects
    0
    0
    0
    Notes
    [9] - Safety population
    No statistical analyses for this end point

    Secondary: Number of subjects with negative NAb result out of ADA positive samples in the safety population

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    End point title
    		 Number of subjects with negative NAb result out of ADA positive samples in the safety population
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline of Cycle 5 (Week 12), Cycle 7 (Week 18), and EOT/ET (Week 24)
    End point values
    		 TX05 Herceptin Safety Population
    Number of subjects analysed
    347
    348
    695 [10]
    Units: Number of subjects
    4
    12
    16
    Notes
    [10] - Safety population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAE in cycles 5 through 8 have been summarized
    Adverse event reporting additional description
    Study drug (TX05/trastuzumab) was not introduced until Cycle 5 of treatment, the analysis of AEs was focused on Cycles 5 through 8 of treatment. The following results include events that occurred on or after initiation of TX05 or Herceptin treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Safety population TX05
    Reporting group description
    		 -

    Reporting group title
    Safety population Herceptin
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population TX05 Safety population Herceptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 394 (2.79%)
    9 / 400 (2.25%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Foetal death
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         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
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiotoxicity
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 400 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 400 (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
    Urinary tract infection
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 Safety population TX05 Safety population Herceptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    246 / 394 (62.44%)
    250 / 400 (62.50%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 394 (6.85%)
    26 / 400 (6.50%)
         occurrences all number
    31
    33
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    33 / 394 (8.38%)
    30 / 400 (7.50%)
         occurrences all number
    40
    41
    Neuropathy peripheral
         subjects affected / exposed
    16 / 394 (4.06%)
    33 / 400 (8.25%)
         occurrences all number
    22
    38
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    30 / 394 (7.61%)
    40 / 400 (10.00%)
         occurrences all number
    46
    65
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 394 (6.60%)
    25 / 400 (6.25%)
         occurrences all number
    31
    26
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    27 / 394 (6.85%)
    31 / 400 (7.75%)
         occurrences all number
    55
    69
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    50 / 394 (12.69%)
    42 / 400 (10.50%)
         occurrences all number
    92
    82
    Myalgia
         subjects affected / exposed
    45 / 394 (11.42%)
    39 / 400 (9.75%)
         occurrences all number
    90
    81

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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