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    Clinical Trial Results:
    Randomised controlled study comparing AEZS-108 with doxorubicin as second line therapy for locally advanced, recurrent or metastatic endometrial cancer (ZoptEC study)

    Summary
    EudraCT number
    		 2012-005546-38
    Trial protocol
    		 CZ   BE   GB   AT   DE   ES   IE   IT   BG   NL   PL   DK   FI  
    Global end of trial date
    02 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2018
    First version publication date
    11 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AEZS-108-050
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01767155
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aeterna Zentaris GmbH
    Sponsor organisation address
    Weismuellerstr. 50, Frankfurt am Main, Germany, 60314
    Public contact
    Clinical trial information desk, Aeterna Zentaris GmbH, +49 69426023429, clinical.trials@aezsinc.com
    Scientific contact
    Clinical trial information desk, Aeterna Zentaris GmbH, +49 69426023429, clinical.trials@aezsinc.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
    01 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the overall survival (OS) of patients treated with AEZS-108 to the overall survival of patients treated with doxorubicin
    Protection of trial subjects
    On a regular basis, results from safety analyses were submitted to an independent Data and Safety Monitoring Board (DSMB) that advised the Sponsor of potentially critical findings. Safety evaluation comprised collection of data related to adverse events, clinical laboratoy parameters, ECGs and data on left ventricular ejection fraction (LVEF).
    Background therapy
    		 No specific background therapy was defined for this trial. One of the eligibilty criteria for this trial was: "No. 5: Patients with advanced, recurrent, or metastatic endometrial cancer who have received one chemotherapeutic regimen with platinum and taxane (either as adjuvant or as first line treatment) and who have progressed." Relevant exclusion criteria in this context: "No. 7: Chemo-, immune-, or hormone-therapy within 5 elimination half-life times or 4 weeks prior to randomization, whichever is the shorter. Radiotherapy (including pre- or post-operative brachytherapy) within 4 weeks prior to randomization. No 8: Previous anthracycline-based chemotherapy (daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone and valrubicin), in any formulation. No 9: Anticipated ongoing concomitant anticancer therapy during the study." All concomitant medications and therapies had to be recorded in the case report form. Permitted therapies defined in the protocol included antiemetics, anti-allergic treatments, hematopoietic blood components in case of delayed hematological recovery, colony stimulation factors, as well as supportive and palliative treatment without any anticancer effect. Prohibited therapies included concomitant anticancer therapies, live vaccines, amiodarone, and sotalol.
    Evidence for comparator
    		 In recent years, there has been a trend towards use of carboplatin/taxane for first line chemotherapy, so that doxorubicin whether as non-liposomal or pegylated liposomal doxorubicin (PLD) formulation is increasingly used in second line chemotherapy. Moderate response rates, however, have been reported for PLD when used in patients with prior chemotherapy (9 %), but also in patients without prior chemotherapy (11.5%), which could have been due to the selection of patients with less favorable prognosis for the latter trial. Based on the reported moderate activity of PLD when used for second line therapy of endometrial cancer, non-liposomal doxorubicin has been selected as comparator drug in this trial. The selection of doxorubicin as comparator drug in this trial implies that prior use of doxorubicin for advanced/recurrent disease was excluded.
    Actual start date of recruitment
    31 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 26 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 6
    Country: Number of subjects enrolled
    Belarus: 9
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 43
    Country: Number of subjects enrolled
    Ukraine: 31
    Country: Number of subjects enrolled
    United States: 140
    Worldwide total number of subjects
    511
    EEA total number of subjects
    218
    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)
    266
    From 65 to 84 years
    245
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The 511 patients who received treatment were enrolled in a total of 112 study centers in Europe, North America, and Israel.

    Pre-assignment
    Screening details
    		 Overall, 592 patients were screened and, of these, 81 patients failed the screening criteria and did not receive treatment with study medication.

    Pre-assignment period milestones
    Number of subjects started
    		 511
    Number of subjects completed
    		 511

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AEZS-108 / Zoptarelin Doxorubicin
    Arm description
    		 - Experimental: AEZS-108 / zoptarelin doxorubicin - 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles - up to 9 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoptarelin doxorubicin
    Investigational medicinal product code
    AEZS-108
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles for a maximum of 9 cycles

    Arm title
    		 Doxorubicin
    Arm description
    		 Active Comparator, standard chemotherapy 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

    Number of subjects in period 1
    		AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Started
    256
    255
    Modified Intention to Treat (mITT)
    252
    249
    Safety Population (SAF)
    252
    249
    Completed
    243
    240
    Not completed
    13
    15
         Protocol deviation
    13
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AEZS-108 / Zoptarelin Doxorubicin
    Reporting group description
    		 - Experimental: AEZS-108 / zoptarelin doxorubicin - 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles - up to 9 cycles

    Reporting group title
    Doxorubicin
    Reporting group description
    		 Active Comparator, standard chemotherapy 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

    Reporting group values
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin Total
    Number of subjects
    		 256 255 511
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 130 136 266
        From 65-84 years
    		 126 119 245
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ± 8.63 63.8 ± 8.81 -
    Gender categorical
    Units: Subjects
        Female
    		 256 255 511
        Male
    		 0 0 0
    ECOG PS
    Eastern Cooperation Oncology Group Performance Status
    Units: Subjects
        Grade 0
    		 120 125 245
        Grade 1
    		 121 118 239
        Grade 2
    		 15 11 26
        Grade unknown
    		 0 1 1
    Stage of endometrial cancer at study entry
    Advanced disease stage comprising FIGO (The International Federation of Gynecology and Obstetrics) III or IV
    Units: Subjects
        Advanced (FIGO III or IV)
    		 99 94 193
        Metastatic
    		 86 90 176
        Recurrent
    		 71 71 142
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population included all randomized patients. Analyses of this population assigned patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Subject analysis sets values
    		 Intention-to-treat (ITT)
    Number of subjects
    511
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    266
        From 65-84 years
    245
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.7 ± 8.71
    Gender categorical
    Units: Subjects
        Female
    511
        Male
    0
    ECOG PS
    Eastern Cooperation Oncology Group Performance Status
    Units: Subjects
        Grade 0
    245
        Grade 1
    239
        Grade 2
    26
        Grade unknown
    1
    Stage of endometrial cancer at study entry
    Advanced disease stage comprising FIGO (The International Federation of Gynecology and Obstetrics) III or IV
    Units: Subjects
        Advanced (FIGO III or IV)
    193
        Metastatic
    176
        Recurrent
    142

    End points

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    End points reporting groups
    Reporting group title
    AEZS-108 / Zoptarelin Doxorubicin
    Reporting group description
    		 - Experimental: AEZS-108 / zoptarelin doxorubicin - 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles - up to 9 cycles

    Reporting group title
    Doxorubicin
    Reporting group description
    		 Active Comparator, standard chemotherapy 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

    Subject analysis set title
    Intention-to-treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population included all randomized patients. Analyses of this population assigned patients the treatment they were scheduled to receive, regardless of any errors of dosing or dose modifications.

    Primary: Compare the Overall Survival (OS) of Patients Treated With AEZS-108 to the OS of Patients Treated With Doxorubicin

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    End point title
    		 Compare the Overall Survival (OS) of Patients Treated With AEZS-108 to the OS of Patients Treated With Doxorubicin
    End point description
    Overall survival was defined as the elapsed time from randomization to death from any cause. For surviving patients, follow-up was to be censored at the date of last contact. The final analysis, which was event-based, was conducted after approximately 384 randomized patients had died. A log-rank test with an overall two sided Type I Error rate of 0.05 after taking the interim analyses into account was used to compare OS between the two treatment arms via a SAS LIFETEST procedure.
    End point type
    Primary
    End point timeframe
    3 years
    End point values
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Number of subjects analysed
    256
    255
    Units: Events
        Survival Events
    196
    188
        Censored
    60
    67
        Survivors at 6 months
    171
    174
        Survivors at 12 months
    111
    106
    Statistical analysis title
    		 Hazard ratio
    Statistical analysis description
    A Cox model with treatment effects was used to estimate the hazard ratio and perform hypothesis testing. The estimated hazard ratio and the 95% CI of the hazard ratio were presented.
    Comparison groups
    AEZS-108 / Zoptarelin Doxorubicin v Doxorubicin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5441
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.3

    Secondary: Compare Efficacy Based on Objective Response Rate (ORR)

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    End point title
    		 Compare Efficacy Based on Objective Response Rate (ORR)
    End point description
    The ORR was defined as the sum of the Complete Response (CR) and Partial Response (PR). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All responses were confirmed at least 4 weeks after the initial response was observed. Tumor assessments occurred every 3 cycles (± 7 days) during ongoing treatment then every 3 months (± 7 days) thereafter while the patient was on study. The last assessment occurred either when progression was confirmed or when approximately 384 randomized patients had died.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Number of subjects analysed
    256
    255
    Units: Subjects
        Complete Response (CR)
    6
    5
        Partial Response (PR)
    26
    31
        Objective Response Rate (ORR)
    32
    36
    Statistical analysis title
    		 Compare Efficacy based on ORR
    Statistical analysis description
    Hypothesis testing between the two treatment arms was performed using a Mantel Haenszel test. The odds ratio and 95% CI of the odds ratio were presented.
    Comparison groups
    AEZS-108 / Zoptarelin Doxorubicin v Doxorubicin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5907
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.45

    Secondary: Compare Efficacy Based on Progression-free Survival (PFS)

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    End point title
    		 Compare Efficacy Based on Progression-free Survival (PFS)
    End point description
    Progression-free survival (PFS) was defined as the days between randomization and the date of documented progression or death for any cause. For patients whose progression status could not be determined, their PFS data was censored for the last adequate progression assessment date that the patient was confirmed to have no progression.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Number of subjects analysed
    256
    255
    Units: Subjects
        PFS events
    166
    148
        Censored
    90
    107
        Survivors at 6 months
    69
    51
        Survivors at 12 months
    28
    12
    Statistical analysis title
    		 Compare Efficacy based on PFS
    Statistical analysis description
    Hypothesis testing between the two treatment arms was performed using a log rank test.
    Comparison groups
    AEZS-108 / Zoptarelin Doxorubicin v Doxorubicin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3089
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.11

    Secondary: Compare Efficacy Based on Clinical Benefit Rate (CBR)

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    End point title
    		 Compare Efficacy Based on Clinical Benefit Rate (CBR)
    End point description
    Clinical benefit was defined as having stable disease (SD) or better lasting for at least 9 weeks. The CBR was analyzed using the same methods for the ORR analyses. The analysis of CBR (CR+PR+SD) was performed in the ITT population. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) was to have a reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Number of subjects analysed
    256
    255
    Units: Subjects
        CR
    6
    5
        PR
    26
    31
        SD
    106
    102
        Progressive Disease (PD)
    65
    67
    Statistical analysis title
    		 Compare Efficacy based on CBR
    Statistical analysis description
    Hypothesis testing between the two treatment arms was performed using a Mantel Haenszel test.
    Comparison groups
    AEZS-108 / Zoptarelin Doxorubicin v Doxorubicin
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6924 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.52
    Notes
    [1] - 2-sided test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall ca. 3 years. SAEs occurring or observed from the day of first administration of the investigational drug on and until 4 weeks after last administration (development of imparied cardiac function within 1 year after last IMP).
    Adverse event reporting additional description
    The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 4.03 or subsequent ones) were to be used for the grading of severity of symptoms and abnormal findings.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    AEZS-108 / Zoptarelin Doxorubicin
    Reporting group description
    		 - 267 mg/m^2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles up to 9 cycles - AEZS-108 / zoptarelin doxorubicin: 267 mg/m2 by 2-hour intravenous infusion, on Day 1 of 21-day (3-week) - cycles for a maximum of 9 cycles

    Reporting group title
    Doxorubicin
    Reporting group description
    		 - 60 mg/m^2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles - doxorubicin: 60 mg/m2 by intravenous bolus injection or 1-hour intravenous infusion, on Day 1 of 21-day (3-week) cycles

    Serious adverse events
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    92 / 252 (36.51%)
    75 / 249 (30.12%)
         number of deaths (all causes)
    196
    188
         number of deaths resulting from adverse events
    3
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    21 / 252 (8.33%)
    15 / 249 (6.02%)
         occurrences causally related to treatment / all
    21 / 21
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    17 / 252 (6.75%)
    8 / 249 (3.21%)
         occurrences causally related to treatment / all
    17 / 17
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    16 / 252 (6.35%)
    9 / 249 (3.61%)
         occurrences causally related to treatment / all
    15 / 16
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 252 (3.17%)
    3 / 249 (1.20%)
         occurrences causally related to treatment / all
    8 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 249 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 252 (4.37%)
    8 / 249 (3.21%)
         occurrences causally related to treatment / all
    6 / 11
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    5 / 252 (1.98%)
    3 / 249 (1.20%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 249 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AEZS-108 / Zoptarelin Doxorubicin Doxorubicin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    245 / 252 (97.22%)
    245 / 249 (98.39%)
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    134 / 252 (53.17%)
    128 / 249 (51.41%)
         occurrences all number
    134
    128
    Anemia
         subjects affected / exposed
    121 / 252 (48.02%)
    111 / 249 (44.58%)
         occurrences all number
    121
    111
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    135 / 252 (53.57%)
    143 / 249 (57.43%)
         occurrences all number
    135
    143

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2013
    Further clarifications on Inclusion criterion #5 and Exclusion criterion #6, #7, #8, #14, and #19. Clarification of timing of cardiac function tests. Clarification of drug reconstitution instructions and dosing calculations. Modification of SAE reporting. Allowed lifetime dose for doxorubicin increased.
    12 Sep 2014
    Addition of global and sparse PK assessments

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

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