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    Clinical Trial Results:
    CONKO-005: Adjuvante Therapie des R0-resezierten Pankreaskarzinoms mit Gemcitabin plus Erlotinib versus Gemcitabin über 24 Wochen – eine prospektive, randomisierte, Phase III Studie

    Summary
    EudraCT number
    		 2007-003813-15
    Trial protocol
    		 DE  
    Global end of trial date
    10 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2021
    First version publication date
    26 Dec 2021
    Other versions
    Summary report(s)
    		 Final report CONKO-005/ML20797

    Trial information

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    Trial identification
    Sponsor protocol code
    CONKO-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité, Campus Virchow Klinikum
    Sponsor organisation address
    Augustenburger Platz 1, Berlin, Germany, 13353
    Public contact
    Prof. Dr. med. Hanno Riess, Charité, Campus Virchow Klinikum Med. Klinik m.S. Hämat./Onkol., 030 450553013, hanno.riess@charite.de
    Scientific contact
    Prof. Dr. med. Hanno Riess, Charité, Campus Virchow Klinikum Med. Klinik m.S. Hämat./Onkol., 030 450553013, hanno.riess@charite.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the disease free survival (DFS) in both treatment groups and to improve survival in patients with pancreatic ductal adenocarcinoma (PDAC) and R0 resection after curatively intended surgery by the addition of the EGFR-tyrosine kinase inhibitor Erlotinib to the standard adjuvant therapy with Gemcitabine. Erlotinib had shown efficacy in metastatic pancreatic cancer patients (Moore et al. 2007) and was estimated to improve survival in primarily resectable pancreatic cancer patients as well.
    Protection of trial subjects
    All data documented in the CRF that describe the population sample characteristics, efficacy and toxicity were evaluated descriptively. One prospectively defined subgroup analysis was to examine the association of EGFR-related skin rash of NCI- CTC grade ≥2 with DFS in the gemcitabine/erlotinib group. Additional subgroup analyses were planned regarding tumor size (T1/T2 vs. T3/T4), Karnofsky performance status at time of randomization (<90% vs 90–100%), CA 19-9 levels (<100 kU/l vs 101-500 kU/l vs > 500 kU/l) at study entry and start of chemotherapy (<= 6 weeks vs >6 weeks after operation).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 436
    Worldwide total number of subjects
    436
    EEA total number of subjects
    436
    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)
    336
    From 65 to 84 years
    100
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pancreatic cancer patients after curatively intended surgery and R0 resection; Further selection details for main inclusion/exclusion criteria see: Finalreport_CONKO-005.

    Pre-assignment
    Screening details
    		 436 patients were randomized by 57 study centers between April 2008 and July 2013

    Period 1
    Period 1 title
    Treatment over 24 weeks (6 cycles) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (GemErlo)
    Arm description
    		 Erlotinib+ Gemcitabine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    n/a L01XX34
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib 100 mg 1x daily orally + Gemcitabine 1000 mg/m² day 1, 8,15, q 29

    Arm title
    		 Arm B (Gem)
    Arm description
    		 Gemcitabine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine hydrochloride
    Investigational medicinal product code
    122111039
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Gemcitabine 1000 mg/m² i.v. day 1, 8, 15, q 29

    Number of subjects in period 1
    		Arm A (GemErlo) Arm B (Gem)
    Started
    219
    217
    Completed
    145
    160
    Not completed
    74
    57
         Adverse event, serious fatal
    4
    2
         Adverse event, non-fatal
    36
    29
         Protocol deviation
    34
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (GemErlo)
    Reporting group description
    		 Erlotinib+ Gemcitabine

    Reporting group title
    Arm B (Gem)
    Reporting group description
    		 Gemcitabine

    Reporting group values
    		 Arm A (GemErlo) Arm B (Gem) Total
    Number of subjects
    		 219 217 436
    Age categorical
    Units: Subjects
        Age between 18-85
    		 219 217 436
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 63 (28 to 82) 65 (24 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 91 98 189
        Male
    		 128 119 247
    Primary tumor size
    Units: Subjects
        T1/T2
    		 27 30 57
        T3/T4
    		 192 187 379
    Nodal status
    Units: Subjects
        N0
    		 79 73 152
        N+
    		 140 144 284
    Tumor grade
    Units: Subjects
        G1
    		 8 9 17
        G2
    		 132 128 260
        G3
    		 72 74 146
        Unkown
    		 7 6 13
    Time surgery to start chemotherapy
    Median (days): GemErlo 47 Gem 42
    Units: Subjects
        2-4 weeks
    		 12 16 28
        5-6 week
    		 60 94 154
        7+ weeks
    		 139 105 244
        No treatment
    		 8 2 10
    Type of surgery
    Units: Subjects
        Pancreatic head resection
    		 175 180 355
        Pancreatic tail resection
    		 30 25 55
        Total pancreatectomy
    		 14 12 26
    Resected in a center with
    Units: Subjects
        < 12 patients
    		 115 101 216
        >=12 patients
    		 104 116 220
    KPS
    Karnofsky performance status.
    Units: Scale
        median (full range (min-max))
    		 90 (60 to 100) 90 (60 to 100) -
    Postoperative CA 19-9
    See for more details: Online references http://www.ncbi.nlm.nih.gov/pubmed/28817370
    Units: kU/L
        median (full range (min-max))
    		 19 (1 to 5816) 18 (1 to 3079) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A (GemErlo)
    Reporting group description
    		 Erlotinib+ Gemcitabine

    Reporting group title
    Arm B (Gem)
    Reporting group description
    		 Gemcitabine

    Primary: Disease-free survival (DFS)

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    End point title
    		 Disease-free survival (DFS)
    End point description
    Estimated DFS rates at 12, 24, and 60 months were 48%, 25%, and 12% (47%, 26%, and 13% in the GemErlo arm; 48%, 25%, and 11% in the Gem arm).
    End point type
    Primary
    End point timeframe
    From baseline to month 60
    End point values
    		 Arm A (GemErlo) Arm B (Gem)
    Number of subjects analysed
    219
    217
    Units: Months
    median (full range (min-max))
        95% confidence interval
    11.4 (9.6 to 13.2)
    11.4 (9.2 to 13.6)
    Attachments
    		 DFS and OSP
    Statistical analysis title
    		 Calculation of the sample size (exponential model)
    Statistical analysis description
    The primary endpoint disease-free survival was defined as time from randomization to first recurrence of disease or death from any cause. The test for significance was based on the log-rank test, for a one-sided significance level of 5% with a power of 80%.
    Comparison groups
    Arm A (GemErlo) v Arm B (Gem)
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.26 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - the analysis of the primary end point was tested one sided
    [2] - All P values were two-sided and unadjusted, according to the trial protocol.

    Secondary: DFS and OS for Different CA 19-9 Levels After Surgery

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    End point title
    		 DFS and OS for Different CA 19-9 Levels After Surgery
    End point description
    Disease-Free Survival (DFS); Overall Survival (OS); For 336 patients with cancer antigen 19-9 (CA 19-9) levels <=100 kU/L (167 patients in the GemErlo arm and 169 in the Gem arm), median DFS was 12.2 months in the GemErlo arm versus 13.1 months in the Gem arm (P = .626); median OS was 27.6 versus 30.1 months (P = .849). Fifty-four patients with postoperatively increased CA 19-9 had a significantly reduced median DFS and OS (P , .001); this effect was comparable in both arms. (Table 3. Diseaseas-Free Survival and Overall Survial for Different CA 19-9 Levels After Surgery; Fig 3. (A) Disease-free survival and (B) overall survival for different CA 19-9 levels after surgery.
    End point type
    Secondary
    End point timeframe
    from baseline to month 60
    End point values
    		 Arm A (GemErlo) Arm B (Gem)
    Number of subjects analysed
    219
    217
    Units: Months
    median (full range (min-max))
        Median DFS <= 100
    12.2 (9.8 to 14.5)
    13.1 (10.6 to 15.6)
        Median DFS 101 to 500
    6.0 (4.2 to 7.8)
    9.0 (6.3 to 11.7)
        Median DFS >500
    5.5 (0.5 to 10.45)
    3.2 (0 to 7.4)
        Median OS <= 100
    27.6 (22.7 to 32.5)
    30.1 (26.3 to 33.8)
        Median OS 101 to 500
    15.6 (10 to 21.2)
    16.4 (15.2 to 17.7)
        Median OS >500
    9.3 (9.2 to 9.5)
    11.9 (0 to 27.3)
    Attachments
    		 (A) Disease-free survival and (B) overall survival
    Disease-Free Survival and Overall Survival for Dif
    Statistical analysis title
    		 Survival probability estimated with the Kaplan-Mei
    Statistical analysis description
    The test for significance was based on the log-rank test, for a one-sided significance level of 5% with a power of 80%.
    Comparison groups
    Arm A (GemErlo) v Arm B (Gem)
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.26
    Method
    		 Logrank
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - A sample size of 436 patients was required to detect an improvement in median DFS of 4 months with GemErlo, with a statistical power of 80% and one-sided 5% type I error, and assuming a 10% dropout rate, a 4-year recruitment period, and a follow-up of at least 3 years.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 60 months
    Adverse event reporting additional description
    For detailed AE and SAE see attachment "Final report CONKO-005/ML20797"(Table 2 AE and Table 3 SAE).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 own
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Arm A GemErlo
    Reporting group description
    		 -

    Reporting group title
    Arm B Gem
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A GemErlo Arm B Gem
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 219 (31.05%)
    56 / 217 (25.81%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Overall
    Additional description: All serious adverse events were merged.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    68 / 219 (31.05%)
    56 / 217 (25.81%)
         occurrences causally related to treatment / all
    8 / 83
    17 / 76
         deaths causally related to treatment / all
    1 / 4
    0 / 3
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A GemErlo Arm B Gem
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    208 / 219 (94.98%)
    211 / 217 (97.24%)
    Investigations
    Overall
    Additional description: All none-serious advers events were merged.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    208 / 219 (94.98%)
    211 / 217 (97.24%)
         occurrences all number
    6444
    6772

    More information

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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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28817370
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