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    Clinical Trial Results:
    LUME-Lung 3: A Phase I/II study of continuous oral treatment with BIBF 1120 added to standard gemcitabine/cisplatin therapy in first-line NSCLC patients with squamous cell histology

    Summary
    EudraCT number
    		 2010-019707-32
    Trial protocol
    		 GB   NL   PT   DE   ES  
    Global end of trial date
    17 Jan 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Apr 2022
    First version publication date
    27 Dec 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1199.82
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01346540
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    19 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the Phase I part of the trial was to confirm that a dose of up to 200 mg twice daily (bid) nintedanib (BIBF 1120), added to gemcitabine and cisplatin, was safe and tolerable in patients with stage IIIB/IV or recurrent non-small cell lung cancer (NSCLC) with squamous cell histology.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Nov 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: 6
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    21
    EEA total number of subjects
    11
    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)
    10
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Phase I was open-label, 3+3 dose-confirmation part of the trial aimed to confirm safety of nintedanib to a maximum dose of 200 milligram twice daily given in combination with the standard regimen of gemcitabine and cisplatin. Phase II was to be double-blind, randomised, placebo-controlled part, but this part of the trial was not conducted.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be entered to trial treatment if any one of the specific entry criteria was violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Phase I was the open-label, 3+3 dose-confirmation part.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nintedanib 150 milligram
    Arm description
    		 Patient received 150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle.

    Arm title
    		 Nintedanib 200 milligram
    Arm description
    		 Patient received 200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Number of subjects in period 1 [1]
    		Nintedanib 150 milligram Nintedanib 200 milligram
    Started
    4
    12
    Completed
    1
    0
    Not completed
    3
    12
         Adverse event, serious fatal
    -
    2
         Adverse event, non-fatal
    -
    2
         Progressive disease-RECIST 1.1 criteria
    3
    8
    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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib 150 milligram
    Reporting group description
    		 Patient received 150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Reporting group title
    Nintedanib 200 milligram
    Reporting group description
    		 Patient received 200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Reporting group values
    		 Nintedanib 150 milligram Nintedanib 200 milligram Total
    Number of subjects
    		 4 12 16
    Age categorical
    All patients who received at least one dose of any study medication were included in the Treated Set (TS)
    Units: Subjects
    Age Continuous
    All patients who received at least one dose of any study medication were included in the Treated Set (TS)
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ± 10.9 65.7 ± 5.0 -
    Gender, Male/Female
    All patients who received at least one dose of any study medication were included in the Treated Set (TS)
    Units: Subjects
        Female
    		 0 1 1
        Male
    		 4 11 15

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib 150 milligram
    Reporting group description
    		 Patient received 150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Reporting group title
    Nintedanib 200 milligram
    Reporting group description
    		 Patient received 200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Primary: Number of participants with Dose Limiting Toxicities (DLTs) during first cycle for the determination of the Maximum Tolerated Dose (MTD)

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    End point title
    		 Number of participants with Dose Limiting Toxicities (DLTs) during first cycle for the determination of the Maximum Tolerated Dose (MTD) [1]
    End point description
    DLT: Non-hematological toxicity - Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥3 events excluding transient electrolyte abnormality, hyperuricemia and isolated elevation of gamma-glutamyl trans-peptidase. Gastrointestinal AEs (nausea, vomiting, diarrhoea, abdominal pain) or hypertension of CTCAE Grade ≥3 despite optimal supportive care/intervention. Alanine aminotransferase and or Aspartate aminotransferase elevation of CTCAE Grade ≥3. Haematological toxicity - Uncomplicated CTCAE Grade 4 neutropenia (that was not associated with fever of ≥38.5° Celsius) for >7 days (except during Cycle 1). CTCAE Grade 4 febrile neutropenia associated with fever ≥38.5º Celsius. A decrease in platelet levels to CTCAE Grade 4 or 3 associated with bleeding or requiring transfusion. The inability to resume nintedanib dosing within 14 days of stopping due to drug-related AE was also considered a DLT. All patients who received at least one dose of nintedanib were included in the Safety Set
    End point type
    Primary
    End point timeframe
    Up to 21 days from first drug administration
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 Nintedanib 150 milligram Nintedanib 200 milligram
    Number of subjects analysed
    4 [2]
    12 [3]
    Units: Participants
    0
    0
    Notes
    [2] - Safety Set
    [3] - Safety Set
    No statistical analyses for this end point

    Primary: Maximum Tolerated Dose (MTD) of nintedanib added to cisplatin/gemcitabine based on the occurrence of DLTs during treatment cycle 1.

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    End point title
    		 Maximum Tolerated Dose (MTD) of nintedanib added to cisplatin/gemcitabine based on the occurrence of DLTs during treatment cycle 1. [4]
    End point description
    The MTD was defined as the dose of nintedanib administered with gemcitabine/cisplatin at which no more than 1 of 6 patients experienced DLT (or one dose tier below that dose at which 2 or more of 6 patients experienced DLT) during the first 21-day treatment cycle. Any DLTs experienced after the start of the second treatment period were considered separately. All patients who received at least one dose of nintedanib were included in the Safety Set. 99999:MTD was not determined for this dose group.
    End point type
    Primary
    End point timeframe
    Up to 21 days from first drug administration
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 Nintedanib 150 milligram Nintedanib 200 milligram
    Number of subjects analysed
    4 [5]
    12 [6]
    Units: Milligram
    99999
    200
    Notes
    [5] - Safety Set
    [6] - Safety Set
    No statistical analyses for this end point

    Secondary: Incidence of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00

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    End point title
    		 Incidence of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00
    End point description
    Incidence of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.00 with grade 1-5. For Phase I, all patients who received at least one dose of any study medication were included in the Treated Set.
    End point type
    Secondary
    End point timeframe
    From the first drug administration until 28 days after last study drug administration, up to 804 days
    End point values
    		 Nintedanib 150 milligram Nintedanib 200 milligram
    Number of subjects analysed
    4 [7]
    12 [8]
    Units: Participants
        Grade 1
    0
    0
        Grade 2
    0
    0
        Grade 3
    1
    8
        Grade 4
    3
    2
        Grade 5
    0
    2
    Notes
    [7] - Treated Set
    [8] - Treated Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after last study drug administration, up to 804 days
    Adverse event reporting additional description
    Adverse events ongoing from the end of the treatment visit were also captured.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Nintedanib 200 milligram‌
    Reporting group description
    		 Patient received 200 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Reporting group title
    Nintedanib 150 milligram‌
    Reporting group description
    		 Patient received 150 milligram (mg) Nintedanib (BIBF 1120) soft gelatin capsules, administered orally twice daily until withdrawal criteria were fulfilled along with standard therapy of Gemcitabine and Cisplatin. Gemcitabine was administered as an intravenous infused dose of 1250 milligram per meter squared (mg/m2) on days 1 and 8 of each 21-day treatment cycle. Cisplatin was administered as an intravenous infused dose of 75 mg/m2 given on day 1 of each 21-day treatment cycle.

    Serious adverse events
    		 Nintedanib 200 milligram‌ Nintedanib 150 milligram‌
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 12 (41.67%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    7
    1
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (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
    Thrombocytopenia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (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
    		 Nintedanib 200 milligram‌ Nintedanib 150 milligram‌
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Hypertension
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    10
    0
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Thrombosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 12 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    13
    1
    Chest discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Fatigue
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    4
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    4
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    4
    6
    Dry throat
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 4 (75.00%)
         occurrences all number
    3
    5
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Haemoptysis
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    4
    Nasal congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    Sputum increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Blood albumin decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Blood sodium decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Blood urea increased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Blood uric acid increased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Monocyte count decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Weight decreased
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    4
    2
    White blood cell count decreased
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Dizziness postural
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 4 (50.00%)
         occurrences all number
    2
    4
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Neuralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    5
    2
    Neutropenia
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    7
    3
    Thrombocytopenia
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    4
    6
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Ear discomfort
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    8
    1
    Vertigo
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    8 / 12 (66.67%)
    1 / 4 (25.00%)
         occurrences all number
    16
    3
    Diarrhoea
         subjects affected / exposed
    5 / 12 (41.67%)
    4 / 4 (100.00%)
         occurrences all number
    9
    5
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Gingival pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Mouth haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    9 / 12 (75.00%)
    4 / 4 (100.00%)
         occurrences all number
    18
    11
    Retching
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    Toothache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    8 / 12 (66.67%)
    2 / 4 (50.00%)
         occurrences all number
    28
    14
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Alopecia
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    4
    1
    Eczema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    4
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    Rash maculo-papular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Lower urinary tract symptoms
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Neck pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Periarthritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Sjogren's syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 12 (33.33%)
    4 / 4 (100.00%)
         occurrences all number
    5
    6
    Dehydration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Increased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    This amendment made several changes to the Phase II part of the study that are not relevant here. The changes to the Phase I part of the study are detailed below: Clarification was added that liver function tests were to be carefully monitored during the study to fulfill the reporting requirements for Drug induced liver injury. Clarification in the reporting requirements for serious adverse events related to worsening of underlying disease or other pre-existing conditions were made. Clarification that patient’s tumour assessments should be performed consistently every 6 weeks for as long as the patient is in the study.

    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.
    This trial was prematurely discontinued (Phase II was not conducted) following Sponsor’s decision not to continue the trial in this indication.
    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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