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    Clinical Trial Results:
    phase IIb randomized clinical trial to evaluate the effectiveness of Gemcitabine-Erlotinib vs Gemcitabine-Erlotinib-Capecitabine in patients with metastatic pancreatic cancer.

    Summary
    EudraCT number
    		 2010-022599-30
    Trial protocol
    		 ES  
    Global end of trial date
    08 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Sep 2018
    First version publication date
    08 Sep 2018
    Other versions
    Summary report(s)
    		 Manuscript EJC

    Trial information

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    Trial identification
    Sponsor protocol code
    TTD-10-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo de tratamiento de los Tumores Digestivos
    Sponsor organisation address
    Téllez 30, madrid, Spain, 28007
    Public contact
    Sonia Maciá Escalante, Pivotal, 34 917081250, sonia.macia@pivotal.es
    Scientific contact
    Inmaculada Ruiz Mena, Grupo de Tratamiento de los Tumores Digestivos, 34 913788275, ttd@ttdgroup.org
    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
    29 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Progression free survival
    Protection of trial subjects
    Treatment dose was adjusted in terms of adverse events and weight lose. G-CSF was allowed as prophylaxis. Adjuvant treatment for nausea/vomiting was prescribed if necessary. Symptomatic treatment was recommended for other toxicities including diarrhea or skin toxicity.
    Background therapy
    		 Gemcitabine has been established since its introduction as the standard first-line treatment in patients with locally advanced or metastatic pancreatic cancer. The experience accumulated in the treatment with gemcitabine in patients with pancreatic cancer indicates that the effects of treatment are moderate, with an average survival that varies from 5 to 8 months and survival rates after the first year of treatment of 17-25%. In order to improve the therapeutic efficacy in patients with pancreatic cancer, numerous clinical trials have addressed this issue through the use of treatment regimens based on gemcitabine combined with a second cytotoxic agent.
    Evidence for comparator
    		 Combination of gemcitabine with erlotinib in patients with advanced pancreatic cancer showed statistically significant improvements, compared to treatment with gemcitabine monotherapy, in overall survival, progression-free survival and survival 1 year. In studies based on capecitabine, administered in different schedules: in monotherapy, in combination with gemcitabine, in combination with erlotinib or in combination with erlotinib + gemcitabine, efficacy data and a good toxicity profile were obtained in the treatment of cancer patients of advanced pancreas. Considering the mentioned results (combination of erlotinib + gemcitabine + capecitabine could suppose an improvement in the efficacy of the treatment of patients with advanced pancreatic cancer with respect to the treatments currently available) this randomized phase IIb clinical trial was proposed, and based on the results of the NCIC CTG PA.3 study, the control group will be patients treated with gemcitabine + erlotinib.
    Actual start date of recruitment
    11 Apr 2011
    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
    Spain: 120
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    100
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 120 patients were included; two out of them did not receive any study treatment. ITT included 60 patients at each arm, safety population included 60 patients at control arm and 58 at experimental arm. This was a national study with all patients being included at 23 Spanish sites.

    Pre-assignment
    Screening details
    		 Inclusion criteria: Ability to understand and willingness to sign and give written informed consent, age ≥ 18 years, ECOG 0-2, life expectancy of at least 12 weeks, Patients with metastatic pancreatic adenocarcinoma, measurable disease, not having received previous systemic treatments, good organic function.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable, open label study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 Gemcitabine plus erlotinib ( G(1000 mg/m2, d1,8,15)+E(100 mg, d1–28)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    gemcitabine
    Investigational medicinal product code
    gemcitabine
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m2 days 1, 8 and 15 every 28 days

    Investigational medicinal product name
    erlotinib
    Investigational medicinal product code
    erlotinib
    Other name
    tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, days 1-28

    Arm title
    		 Arm B
    Arm description
    		 Experimental arm, G(1000 mg/m2, d1,8,15)+E(100 mg, d1–28)+C(1660 mg/m2, d1-21)
    Arm type
    		 Experimental

    Investigational medicinal product name
    gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m2

    Investigational medicinal product name
    erlotinib
    Investigational medicinal product code
    Other name
    tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    xeloda
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    850 mg

    Number of subjects in period 1
    		Control Arm B
    Started
    60
    60
    Completed
    60
    58
    Not completed
    0
    2
         Adverse event, non-fatal
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 120 pts were randomized. Median age: 63years; ECOG status0/1/2(%), 33/58/8. 52 women, 68 men. Median weight 67,26 Kg. Median body surface 1,72. Medican time from diagnosis 0,59 months. Diagnosis by histology in 57 patients; citology in 63 patients. Tx in 46 patients; T4 in 29 patients. All patients with metastatic disease. Median metastases location sites 3 (min-max; 1-9). Most common metastases locations: liver (93), regional lymph nodes (54), lung (24), distant lymph nodes (18), omentum (15)

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 120 120
    Age categorical
    Mean age was 61.33, median age 62.50. Min age was 29; maximum age 78
    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)
    		 90 90
        From 65-84 years
    		 30 30
        85 years and over
    		 0 0
    Age continuous
    age for ITT population
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 61 (56 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 52 52
        Male
    		 68 68
    Subject analysis sets

    Subject analysis set title
    control arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    subjects included at control arm, 26 women and 34 men

    Subject analysis set title
    experimental arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    experimental arm, 26 women and 34 men

    Subject analysis sets values
    		 control arm experimental arm
    Number of subjects
    60
    60
    Age categorical
    Mean age was 61.33, median age 62.50. Min age was 29; maximum age 78
    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)
    40
    40
        From 65-84 years
    20
    20
        85 years and over
    0
    0
    Age continuous
    age for ITT population
    Units: years
        median (inter-quartile range (Q1-Q3))
    64 (57 to 70)
    62 (53 to 68)
    Gender categorical
    Units: Subjects
        Female
    26
    26
        Male
    34
    34

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Gemcitabine plus erlotinib ( G(1000 mg/m2, d1,8,15)+E(100 mg, d1–28)

    Reporting group title
    Arm B
    Reporting group description
    		 Experimental arm, G(1000 mg/m2, d1,8,15)+E(100 mg, d1–28)+C(1660 mg/m2, d1-21)

    Subject analysis set title
    control arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    subjects included at control arm, 26 women and 34 men

    Subject analysis set title
    experimental arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    experimental arm, 26 women and 34 men

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    Time from inclusion until the date on which the disease progression or death from any cause is documented (whichever occurs first).
    End point type
    Primary
    End point timeframe
    From inclusion until progressive disease
    End point values
    		 Control Arm B
    Number of subjects analysed
    60 [1]
    60
    Units: months
        median PFS
    3
    4
    Notes
    [1] - 60 patients were included at arm A
    Statistical analysis title
    		 efficacy analysis
    Statistical analysis description
    Primary endpoint is progression-free survival defined as the time from the randomization date to the patient's progression or death from any cause, whichever occurs first. Survival (progression-free and global) in each treatment arm with a Kaplan-Meier life table is described. Median survival is presented for each treatment group with their respective 95% confidence intervals. The analysis between both arms was carried out through the Log-rank test stratified by ECOG.
    Comparison groups
    Control v Arm B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05 [3]
    Method
    		 Logrank
    Parameter type
    		 Median difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 5.6
    Dispersion value
    0.36
    Notes
    [2] - A Cox model was applied to control other prognostic factors, after verifying the assumptions of proportionality through Schoenfeld residuals. In these survival analyzes: • Subjects in whom no evaluations of the tumor are available after the baseline assessment, but who remain alive at the deadline for collection of clinical data were censored on day 1 for SLP and on the date of last contact for SG. • Subjects who have not manifested progression of the disease or who have died were censored.
    [3] - Median survival is presented for each treatment group with their respective 95% confidence intervals.
    Statistical analysis title
    		 PFS depending on rash grade
    Statistical analysis description
    PFS was analyzed depending on the rash grade that patients had presented while on treatment
    Comparison groups
    Control v Arm B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 11.9
    Variability estimate
    Standard deviation

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Since randomization till death due to any reason
    End point values
    		 Control Arm B
    Number of subjects analysed
    60
    60
    Units: months
    median (standard deviation)
        Overall survival
    7.7 ± 0.5
    6.8 ± 0.5
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Best objective response according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    Since first patient in until end of study
    End point values
    		 Control Arm B
    Number of subjects analysed
    60
    60
    Units: patients
    11
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from first patient included (inform consent form signed) until 30 days after last study drug dose was administered
    Adverse event reporting additional description
    A total of 34 patients (57%) in the GE arm and 42 patients (72%) in the GEC arm had grade 3 adverse events related to treatment. Treatment discontinuation due to treatment related adverse events occurred in eight patients in both the GE arm (13%)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Control arm

    Reporting group title
    Arm B
    Reporting group description
    		 experimental arm

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 60 (53.33%)
    25 / 58 (43.10%)
         number of deaths (all causes)
    53
    53
         number of deaths resulting from adverse events
    7
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumor pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    progressive disease
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ischemia periferal
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    General disorders and administration site conditions
    Ascites
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fever
         subjects affected / exposed
    5 / 60 (8.33%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cholangitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    dyspnea
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    weakness
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Diverticulitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    staphilococcus positive
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    testis oedema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic oil syndrome
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    brain stroke
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    febril neutropaenia
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel movement irregularity
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic enteritis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastric haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute abdomen
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intestinal hemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatobiliary disorders
    Pain
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 60 (100.00%)
    58 / 58 (100.00%)
    Vascular disorders
    Cough
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    3
    Embolism
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 58 (5.17%)
         occurrences all number
    5
    3
    Phlebitis
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
         occurrences all number
    2
    4
    Surgical and medical procedures
    Alopecia
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 58 (8.62%)
         occurrences all number
    2
    5
    Skin toxicity
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    41 / 60 (68.33%)
    47 / 58 (81.03%)
         occurrences all number
    41
    47
    pirexia
         subjects affected / exposed
    28 / 60 (46.67%)
    24 / 58 (41.38%)
         occurrences all number
    18
    24
    Mucosal inflammation
         subjects affected / exposed
    13 / 60 (21.67%)
    24 / 58 (41.38%)
         occurrences all number
    13
    24
    Oedema peripheral
         subjects affected / exposed
    13 / 60 (21.67%)
    12 / 58 (20.69%)
         occurrences all number
    13
    12
    Pain
         subjects affected / exposed
    9 / 60 (15.00%)
    7 / 58 (12.07%)
         occurrences all number
    9
    7
    General physical health deterioration
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 58 (10.34%)
         occurrences all number
    4
    6
    Xerosis
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Oedema
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    3
    Social circumstances
    Skin fissures
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
         occurrences all number
    2
    4
    Xeroderma
         subjects affected / exposed
    0 / 60 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    0
    5
    Reproductive system and breast disorders
    Back pain
         subjects affected / exposed
    10 / 60 (16.67%)
    10 / 58 (17.24%)
         occurrences all number
    10
    10
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 58 (6.90%)
         occurrences all number
    7
    4
    Epistaxis
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    Rhinitis
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 60 (11.67%)
    3 / 58 (5.17%)
         occurrences all number
    7
    3
    Insomnia
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 58 (6.90%)
         occurrences all number
    3
    4
    Investigations
    GGT increased
         subjects affected / exposed
    17 / 60 (28.33%)
    5 / 58 (8.62%)
         occurrences all number
    17
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 58 (3.45%)
         occurrences all number
    7
    2
    Weight decreased
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 58 (6.90%)
         occurrences all number
    5
    4
    alkaline phosphatase increased
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 58 (5.17%)
         occurrences all number
    5
    3
    Transaminases increased
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Bilirubin conjugated increased
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 58 (1.72%)
         occurrences all number
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 58 (1.72%)
         occurrences all number
    5
    1
    Nervous system disorders
    Cachexia
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Dysgeusia
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 58 (6.90%)
         occurrences all number
    2
    4
    Dizziness
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Paraesthesia
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 58 (1.72%)
         occurrences all number
    4
    1
    Somnolence
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    21 / 60 (35.00%)
    36 / 58 (62.07%)
         occurrences all number
    21
    36
    anemia
         subjects affected / exposed
    21 / 60 (35.00%)
    29 / 58 (50.00%)
         occurrences all number
    21
    29
    Thrombocytopenia
         subjects affected / exposed
    19 / 60 (31.67%)
    30 / 58 (51.72%)
         occurrences all number
    19
    30
    Leukopenia
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 58 (8.62%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Fatigue
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    28 / 60 (46.67%)
    37 / 58 (63.79%)
         occurrences all number
    28
    37
    Nausea
         subjects affected / exposed
    29 / 60 (48.33%)
    30 / 58 (51.72%)
         occurrences all number
    29
    30
    Vomiting
         subjects affected / exposed
    25 / 60 (41.67%)
    24 / 58 (41.38%)
         occurrences all number
    25
    24
    Constipation
         subjects affected / exposed
    19 / 60 (31.67%)
    25 / 58 (43.10%)
         occurrences all number
    19
    25
    Abdominal pain
         subjects affected / exposed
    18 / 60 (30.00%)
    24 / 58 (41.38%)
         occurrences all number
    18
    24
    Abdominal pain upper
         subjects affected / exposed
    9 / 60 (15.00%)
    13 / 58 (22.41%)
         occurrences all number
    9
    13
    Dyspepsia
         subjects affected / exposed
    7 / 60 (11.67%)
    6 / 58 (10.34%)
         occurrences all number
    7
    6
    Dry mouth
         subjects affected / exposed
    7 / 60 (11.67%)
    4 / 58 (6.90%)
         occurrences all number
    7
    4
    Abdominal distension
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 58 (10.34%)
         occurrences all number
    4
    6
    Ascites
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    Flatulence
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 58 (6.90%)
         occurrences all number
    5
    4
    Cholangitis
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    3
    Liver function test abnormal
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    30 / 60 (50.00%)
    28 / 58 (48.28%)
         occurrences all number
    30
    28
    Palmoplantar keratoderma
         subjects affected / exposed
    2 / 60 (3.33%)
    13 / 58 (22.41%)
         occurrences all number
    2
    13
    Dry skin
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    Onycholysis
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 58 (3.45%)
         occurrences all number
    4
    2
    Musculoskeletal and connective tissue disorders
    limb pain
         subjects affected / exposed
    3 / 60 (5.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Arthralgia
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 58 (8.62%)
         occurrences all number
    1
    5
    muscle pain
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 58 (10.34%)
         occurrences all number
    4
    6
    Cellulitis
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 58 (3.45%)
         occurrences all number
    3
    2
    Paronychia
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 58 (5.17%)
         occurrences all number
    1
    3
    Conjunctivitis
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 58 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    29 / 60 (48.33%)
    30 / 58 (51.72%)
         occurrences all number
    29
    30
    Hyperglycaemia
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 58 (6.90%)
         occurrences all number
    5
    4
    Hypoglycaemia
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jan 2012
    A new exploratory objective was added (peripheral blood analysis to search predictive biomarkers)
    24 Mar 2014
    Trial end date was updated, as "End of trial will be the date when last patient finishes treatment phase due to any reason and after End of Study or early withdrawal visit is performed"

    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.
    The delivered dose intensity of both gemcitabine and erlotinib being lower in the GEC arm, primarily as a result of haematological toxicities; this might explain the treatment with GEC was less effective than expected

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28222309
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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