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    Clinical Trial Results:
    An Open-label, Phase II Study of Vemurafenib in Patients with BRAF V600 Mutation-positive Cancers

    Summary
    EudraCT number
    2011-004426-10
    Trial protocol
    GB   ES   DE  
    Global end of trial date
    27 Oct 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Nov 2017
    First version publication date
    07 Sep 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MO28072
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01524978
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    27 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to assess the efficacy of vemurafenib in subjects with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 103
    Country: Number of subjects enrolled
    France: 63
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    208
    EEA total number of subjects
    105
    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)
    134
    From 65 to 84 years
    71
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    One participant with breast cancer was screened shortly after Cohort 5 (Breast Cancer) had been closed. This participant was allowed to enter the study in Cohort 7: Other BRAF V600-positive tumors. For analysis purposes Cohort 7 was split into sub-cohorts for indications with sufficient participants.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib
    Arm description
    Subjects with NSCLC were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 2: Ovarian Cancer - vemurafenib
    Arm description
    Subjects with ovarian cancer were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 3a: Colorectal Cancer - vemurafenib
    Arm description
    Subjects with colorectal cancer were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Arm description
    Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Escalating doses were given orally twice a day starting on Day 2 of Cycle 1.The escalating doses were as follows: Dose Level 1: 720 mg of vemurafenib; Dose Level 2: 720 mg of vemurafenib; Dose Level 3: 960 mg of vemurafenib.

    Investigational medicinal product name
    cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Escalating doses were administered on Day 1 and then once weekly by intravenous infusion. The escalating doses were as follows: Dose Level 1:300 milligrams per square meter (mg/m^2) loading dose of cetuximab and then 200 mg/m^2 weekly; Dose Level 2: 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly.

    Arm title
    Cohort 4: Cholangiocarcinoma - vemurafenib
    Arm description
    Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 6: Multiple Myeloma - vemurafenib
    Arm description
    Subjects with multiple myeloma were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 7a: ECD/LCH - vemurafenib
    Arm description
    Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib
    Arm description
    Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 7c: Advanced Stage Astrocytoma - vemurafenib
    Arm description
    Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Cohort 7d: Early Stage Astrocytoma - vemurafenib
    Arm description
    Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Arm title
    Other BRAF V600-positive Tumors - vemurafenib
    Arm description
    Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.
    Arm type
    Experimental

    Investigational medicinal product name
    vemurafenib
    Investigational medicinal product code
    Other name
    Zelboraf
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

    Number of subjects in period 1
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Started
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
         Adverse event, serious fatal
    34
    2
    5
    24
    4
    4
    1
    9
    5
    6
    17
         Consent withdrawn by subject
    12
    -
    1
    1
    3
    1
    6
    2
    4
    -
    5
         Unspecified
    16
    2
    1
    2
    1
    3
    17
    1
    2
    2
    5
         Lost to follow-up
    -
    -
    3
    -
    1
    1
    2
    -
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib
    Reporting group description
    Subjects with NSCLC were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 2: Ovarian Cancer - vemurafenib
    Reporting group description
    Subjects with ovarian cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 3a: Colorectal Cancer - vemurafenib
    Reporting group description
    Subjects with colorectal cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Reporting group description
    Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

    Reporting group title
    Cohort 4: Cholangiocarcinoma - vemurafenib
    Reporting group description
    Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 6: Multiple Myeloma - vemurafenib
    Reporting group description
    Subjects with multiple myeloma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7a: ECD/LCH - vemurafenib
    Reporting group description
    Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib
    Reporting group description
    Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7c: Advanced Stage Astrocytoma - vemurafenib
    Reporting group description
    Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7d: Early Stage Astrocytoma - vemurafenib
    Reporting group description
    Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.

    Reporting group title
    Other BRAF V600-positive Tumors - vemurafenib
    Reporting group description
    Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

    Reporting group values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib Total
    Number of subjects
    62 4 10 27 9 9 26 12 12 9 28 208
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    30 4 10 15 8 7 15 6 12 8 19 134
        From 65-84 years
    30 0 0 12 1 2 11 6 0 1 8 71
        85 years and over
    2 0 0 0 0 0 0 0 0 0 1 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65.4 ± 10.2 45.8 ± 5.3 57.3 ± 5.4 64.3 ± 8.8 53.2 ± 9.7 62.1 ± 4.3 60.8 ± 13.3 66.8 ± 9.2 41.6 ± 12.2 34.3 ± 20.7 53.7 ± 17.5 -
    Gender, Male/Female
    Units: Subjects
        Female
    27 4 5 18 5 3 14 3 8 9 15 111
        Male
    35 0 5 9 4 6 12 9 4 0 13 97

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib
    Reporting group description
    Subjects with NSCLC were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 2: Ovarian Cancer - vemurafenib
    Reporting group description
    Subjects with ovarian cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 3a: Colorectal Cancer - vemurafenib
    Reporting group description
    Subjects with colorectal cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Reporting group description
    Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

    Reporting group title
    Cohort 4: Cholangiocarcinoma - vemurafenib
    Reporting group description
    Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 6: Multiple Myeloma - vemurafenib
    Reporting group description
    Subjects with multiple myeloma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7a: ECD/LCH - vemurafenib
    Reporting group description
    Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib
    Reporting group description
    Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7c: Advanced Stage Astrocytoma - vemurafenib
    Reporting group description
    Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.

    Reporting group title
    Cohort 7d: Early Stage Astrocytoma - vemurafenib
    Reporting group description
    Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.

    Reporting group title
    Other BRAF V600-positive Tumors - vemurafenib
    Reporting group description
    Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

    Primary: Confirmed Best Overall Response Rate (BORR)

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    End point title
    Confirmed Best Overall Response Rate (BORR) [1]
    End point description
    Confirmed BORR: percentage of subjects with an objective response (OR) (complete response [CR], partial response [PR], stringent CR [sCR] or very good PR [VGPR]) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. or International Myeloma Working Group (IMWG) criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal free light chain (FLC) ratio and no clonal cells in bone marrow.
    End point type
    Primary
    End point timeframe
    Up to approximately 3 years
    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: Primary efficacy results were summarized by cohort each representing specific cancer types. No statistical analyses were done, since all cohorts received vemurafenib treatment.
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62 [2]
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: percentage of subjects
        number (confidence interval 95%)
    37.1 (25.16 to 50.31)
    50.0 (6.76 to 93.24)
    0 (0.00 to 30.85)
    7.4 (0.91 to 24.29)
    22.2 (2.81 to 60.01)
    22.2 (2.81 to 60.01)
    61.5 (40.57 to 79.77)
    25.0 (5.49 to 57.19)
    16.7 (2.09 to 48.41)
    33.3 (7.49 to 70.07)
    17.9 (6.06 to 36.89)
    Notes
    [2] - Intent-to-Treat (ITT) population included all subjects enrolled in the study.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Confirmed Clinical Benefit

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    End point title
    Percentage of Subjects with Confirmed Clinical Benefit
    End point description
    Confirmed clinical benefit rate: percentage of subjects with confirmed PR or CR or Stable Disease (SD) that have lasted at least 6 months according to RECIST v1.1 or confirmed CR, PR, VGPR, sCR or SD for at least 6 months according to IMWG criteria. RECIST v1.1: PR: >/= 30% decrease in the sum of diameters of target lesions; CR: disappearance of all target lesions; SD: not meeting criteria for CR, PR or progressive disease (PD). IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow; SD: not meeting criteria for CR, VGPR, PR or PD.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62 [3]
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: percentage of subjects
        number (confidence interval 95%)
    48.4 (35.50 to 61.44)
    50.0 (6.76 to 93.24)
    0 (-9999 to 9999)
    18.5 (6.30 to 38.08)
    44.4 (13.70 to 78.80)
    22.2 (2.81 to 60.01)
    76.9 (56.35 to 91.03)
    25.0 (5.49 to 57.19)
    33.3 (9.92 to 65.11)
    44.4 (13.70 to 78.80)
    17.9 (6.06 to 36.89)
    Notes
    [3] - ITT population: all subjects enrolled. (-)9999 = not estimable due to insufficient number of events
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR)
    End point description
    ORR: percentage of subjects with an objective response (OR) (CR, PR, sCR or VGPR) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using RECIST v1.1. or IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal free light chain (FLC) ratio and no clonal cells in bone marrow. ITT population: all subjects enrolled in the study.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62 [4]
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: percentage of subjects
    number (confidence interval 95%)
        CR
    0 (0.00 to 5.78)
    0 (0.00 to 60.24)
    0 (0.00 to 30.85)
    0 (0.00 to 12.77)
    0 (0.00 to 33.63)
    0 (0.00 to 33.63)
    7.7 (0.95 to 25.13)
    8.3 (0.21 to 38.48)
    8.3 (0.21 to 38.48)
    0 (0.00 to 33.63)
    3.6 (0.09 to 18.35)
        PR
    37.1 (25.16 to 50.31)
    50.0 (6.76 to 93.24)
    0 (0.00 to 30.85)
    7.4 (0.91 to 24.29)
    22.2 (2.81 to 60.01)
    11.1 (0.28 to 48.25)
    53.8 (33.37 to 73.41)
    16.7 (2.09 to 48.41)
    8.3 (0.21 to 38.48)
    33.3 (7.49 to 70.07)
    14.3 (4.03 to 32.67)
        VGPR
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    11.1 (0.28 to 48.25)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
        sCR
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    0 (0.00 to 33.63)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [4] - 9999 = not evaluated (only in Cohort 6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    DOR was defined as the period from the date of initial PR or CR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria, until the date of PD or death from any cause. RECIST v1.1: PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    2
    9
    28
    Units: months
        median (confidence interval 95%)
    7.16 (5.49 to 18.43)
    8.16 (3.88 to 12.45)
    9999 (9999 to 9999)
    6.54 (5.68 to 7.39)
    12.86 (3.58 to 22.14)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9.95 (8.31 to 30.98)
    9999 (13.08 to 9999)
    3.42 (2.40 to 7.49)
    9.92 (3.48 to 21.22)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was defined as the time from the first day of study treatment to the date of first CR, or PR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions. IMWG criteria: CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to < 200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow. ITT population: all subjects enrolled in the study. (-)9999 = not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: months
        median (confidence interval 95%)
    7.26 (3.68 to 9999)
    9999 (1.64 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (3.52 to 9999)
    5.75 (-9999 to 9999)
    5.49 (3.68 to 13.73)
    9999 (1.68 to 9999)
    9999 (1.74 to 9999)
    9999 (2.33 to 9999)
    9999 (3.68 to 9999)
    No statistical analyses for this end point

    Secondary: Time to Tumor Progression (TTP)

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    End point title
    Time to Tumor Progression (TTP)
    End point description
    TTP was defined as time from the first day of study treatment to the first occurrence of progressive disease (PD). RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: months
        median (confidence interval 95%)
    7.33 (5.29 to 9.66)
    6.44 (1.87 to 14.29)
    3.88 (1.84 to 5.52)
    3.68 (3.45 to 5.39)
    3.02 (1.64 to 9.00)
    4.63 (2.89 to 9999)
    9999 (9999 to 9999)
    2.83 (1.77 to 5.49)
    5.62 (1.81 to 14.85)
    5.36 (3.02 to 9.10)
    3.65 (1.68 to 5.75)
    No statistical analyses for this end point

    Secondary: Progression free Survival (PFS)

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    End point title
    Progression free Survival (PFS)
    End point description
    PFS was defined as the time from the first day of study treatment, until the first documented PD or death from any cause, whichever occurs first. RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG criteria: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: months
        median (confidence interval 95%)
    6.51 (5.16 to 8.97)
    6.44 (1.87 to 14.29)
    3.88 (1.84 to 5.52)
    3.68 (1.81 to 5.39)
    3.02 (1.64 to 9.00)
    4.63 (2.89 to 9999)
    9999 (9999 to 9999)
    2.83 (1.77 to 5.49)
    9.59 (1.81 to 14.78)
    5.26 (3.02 to 5.72)
    3.12 (1.64 to 5.55)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as time between the first day of study treatment and date of death of any cause. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: months
        median (confidence interval 95%)
    15.38 (9.56 to 22.77)
    9999 (2.56 to 9999)
    9.30 (7.82 to 12.88)
    7.16 (5.49 to 11.73)
    17.94 (11.20 to 9999)
    24.54 (4.96 to 9999)
    9999 (9999 to 9999)
    5.88 (2.17 to 16.79)
    40.11 (9.59 to 40.11)
    12.75 (6.70 to 9999)
    11.56 (3.71 to 28.16)
    No statistical analyses for this end point

    Secondary: Maximum Tolerated Dose for Vemurafenib in Combination with Cetuximab

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    End point title
    Maximum Tolerated Dose for Vemurafenib in Combination with Cetuximab
    End point description
    Cohort 3b included subjects with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are the maximum tolerated doses for each vemurafenib and cetuximab. The safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    14
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: milligrams (mg)
        vemurafenib
    960
        cetuximab
    400
    Notes
    [5] - Endpoint only applies to combination therapy in cohort 3b.
    [6] - Endpoint only applies to combination therapy in cohort 3b.
    [7] - Endpoint only applies to combination therapy in cohort 3b.
    [8] - Endpoint only applies to combination therapy in cohort 3b.
    [9] - Endpoint only applies to combination therapy in cohort 3b.
    [10] - Endpoint only applies to combination therapy in cohort 3b.
    [11] - Endpoint only applies to combination therapy in cohort 3b.
    [12] - Endpoint only applies to combination therapy in cohort 3b.
    [13] - Endpoint only applies to combination therapy in cohort 3b.
    [14] - Endpoint only applies to combination therapy in cohort 3b.
    No statistical analyses for this end point

    Secondary: Number of Dose-limiting Toxicities of Vemurafenib in Combination with Cetuximab

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    End point title
    Number of Dose-limiting Toxicities of Vemurafenib in Combination with Cetuximab
    End point description
    Cohort 3b included subjects with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are type and number of dose limited toxicities observed. The safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    14
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    Units: dose-limiting toxicities
        Grade 3 amylase increased
    1
        Grade 4 lipase increased
    1
    Notes
    [15] - Endpoint only applies to combination therapy in cohort 3b.
    [16] - Endpoint only applies to combination therapy in cohort 3b.
    [17] - Endpoint only applies to combination therapy in cohort 3b.
    [18] - Endpoint only applies to combination therapy in cohort 3b.
    [19] - Endpoint only applies to combination therapy in cohort 3b.
    [20] - Endpoint only applies to combination therapy in cohort 3b.
    [21] - Endpoint only applies to combination therapy in cohort 3b.
    [22] - Endpoint only applies to combination therapy in cohort 3b.
    [23] - Endpoint only applies to combination therapy in cohort 3b.
    [24] - Endpoint only applies to combination therapy in cohort 3b.
    No statistical analyses for this end point

    Secondary: Safety: Percentage of Subjects with Adverse Event

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    End point title
    Safety: Percentage of Subjects with Adverse Event
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety population included all subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3 years
    End point values
    Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib Cohort 2: Ovarian Cancer - vemurafenib Cohort 3a: Colorectal Cancer - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab Cohort 4: Cholangiocarcinoma - vemurafenib Cohort 6: Multiple Myeloma - vemurafenib Cohort 7a: ECD/LCH - vemurafenib Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib Cohort 7c: Advanced Stage Astrocytoma - vemurafenib Cohort 7d: Early Stage Astrocytoma - vemurafenib Other BRAF V600-positive Tumors - vemurafenib
    Number of subjects analysed
    62
    4
    10
    27
    9
    9
    26
    12
    12
    9
    28
    Units: percentage of subjects
        number (not applicable)
    100
    100
    100
    100
    100
    100
    100
    91.7
    100
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to approximately 3 years
    Adverse event reporting additional description
    The safety population included all subjects who received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Pooled arm - vemurafenib
    Reporting group description
    Subjects with a variety of cancer types, who were treated with vemurafenib monotherapy, were combined into this arm.

    Reporting group title
    Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Reporting group description
    Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

    Serious adverse events
    Pooled arm - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    91 / 181 (50.28%)
    11 / 27 (40.74%)
         number of deaths (all causes)
    87
    25
         number of deaths resulting from adverse events
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    25 / 181 (13.81%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    38 / 39
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    18 / 181 (9.94%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    28 / 28
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    7 / 181 (3.87%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    11 / 13
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    4 / 181 (2.21%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraganglion neoplasm
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Prostatitis
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Pseudolymphoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Laryngeal dyspnoea
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Iridocyclitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 181 (2.21%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder dilatation
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Diabetes mellitus
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    6 / 181 (3.31%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 181 (2.76%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 181 (2.21%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 181 (1.66%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 27 (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
    Pooled arm - vemurafenib Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 181 (97.79%)
    26 / 27 (96.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 181 (15.47%)
    3 / 27 (11.11%)
         occurrences all number
    38
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Melanocytic naevus
         subjects affected / exposed
    41 / 181 (22.65%)
    4 / 27 (14.81%)
         occurrences all number
    67
    4
    Seborrhoeic keratosis
         subjects affected / exposed
    36 / 181 (19.89%)
    3 / 27 (11.11%)
         occurrences all number
    49
    3
    Skin papilloma
         subjects affected / exposed
    50 / 181 (27.62%)
    7 / 27 (25.93%)
         occurrences all number
    86
    8
    Papilloma
         subjects affected / exposed
    17 / 181 (9.39%)
    0 / 27 (0.00%)
         occurrences all number
    21
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    39 / 181 (21.55%)
    10 / 27 (37.04%)
         occurrences all number
    44
    13
    Chest pain
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Chills
         subjects affected / exposed
    10 / 181 (5.52%)
    2 / 27 (7.41%)
         occurrences all number
    10
    2
    Fatigue
         subjects affected / exposed
    60 / 181 (33.15%)
    6 / 27 (22.22%)
         occurrences all number
    68
    8
    Oedema peripheral
         subjects affected / exposed
    21 / 181 (11.60%)
    4 / 27 (14.81%)
         occurrences all number
    25
    4
    Pyrexia
         subjects affected / exposed
    26 / 181 (14.36%)
    5 / 27 (18.52%)
         occurrences all number
    30
    11
    Cyst
         subjects affected / exposed
    21 / 181 (11.60%)
    0 / 27 (0.00%)
         occurrences all number
    26
    0
    Xerosis
         subjects affected / exposed
    16 / 181 (8.84%)
    0 / 27 (0.00%)
         occurrences all number
    18
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    14 / 181 (7.73%)
    2 / 27 (7.41%)
         occurrences all number
    14
    2
    Depression
         subjects affected / exposed
    10 / 181 (5.52%)
    3 / 27 (11.11%)
         occurrences all number
    10
    5
    Insomnia
         subjects affected / exposed
    18 / 181 (9.94%)
    0 / 27 (0.00%)
         occurrences all number
    19
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Sunburn
         subjects affected / exposed
    22 / 181 (12.15%)
    4 / 27 (14.81%)
         occurrences all number
    27
    4
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 181 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    0
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 181 (8.29%)
    2 / 27 (7.41%)
         occurrences all number
    15
    2
    Blood bilirubin increased
         subjects affected / exposed
    10 / 181 (5.52%)
    3 / 27 (11.11%)
         occurrences all number
    14
    3
    Electrocardiogram QT prolonged
         subjects affected / exposed
    37 / 181 (20.44%)
    4 / 27 (14.81%)
         occurrences all number
    52
    4
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    6
    Lipase increased
         subjects affected / exposed
    10 / 181 (5.52%)
    9 / 27 (33.33%)
         occurrences all number
    21
    10
    Weight decreased
         subjects affected / exposed
    20 / 181 (11.05%)
    6 / 27 (22.22%)
         occurrences all number
    20
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 181 (8.29%)
    0 / 27 (0.00%)
         occurrences all number
    17
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 181 (6.08%)
    0 / 27 (0.00%)
         occurrences all number
    12
    0
    Blood creatinine increased
         subjects affected / exposed
    19 / 181 (10.50%)
    0 / 27 (0.00%)
         occurrences all number
    26
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 181 (16.57%)
    3 / 27 (11.11%)
         occurrences all number
    40
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 181 (17.13%)
    2 / 27 (7.41%)
         occurrences all number
    42
    4
    Dysphonia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    22 / 181 (12.15%)
    5 / 27 (18.52%)
         occurrences all number
    27
    7
    Nasal congestion
         subjects affected / exposed
    10 / 181 (5.52%)
    0 / 27 (0.00%)
         occurrences all number
    11
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 181 (14.36%)
    4 / 27 (14.81%)
         occurrences all number
    30
    5
    Dysgeusia
         subjects affected / exposed
    24 / 181 (13.26%)
    0 / 27 (0.00%)
         occurrences all number
    25
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    27 / 181 (14.92%)
    0 / 27 (0.00%)
         occurrences all number
    27
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    11 / 181 (6.08%)
    0 / 27 (0.00%)
         occurrences all number
    11
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 181 (6.63%)
    12 / 27 (44.44%)
         occurrences all number
    13
    18
    Abdominal pain upper
         subjects affected / exposed
    0 / 181 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    4
    Constipation
         subjects affected / exposed
    26 / 181 (14.36%)
    5 / 27 (18.52%)
         occurrences all number
    30
    6
    Diarrhoea
         subjects affected / exposed
    49 / 181 (27.07%)
    13 / 27 (48.15%)
         occurrences all number
    67
    30
    Dyspepsia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Flatulence
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    5
    Nausea
         subjects affected / exposed
    54 / 181 (29.83%)
    9 / 27 (33.33%)
         occurrences all number
    80
    13
    Rectal haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Stomatitis
         subjects affected / exposed
    19 / 181 (10.50%)
    4 / 27 (14.81%)
         occurrences all number
    20
    5
    Vomiting
         subjects affected / exposed
    41 / 181 (22.65%)
    8 / 27 (29.63%)
         occurrences all number
    55
    10
    Dry mouth
         subjects affected / exposed
    12 / 181 (6.63%)
    0 / 27 (0.00%)
         occurrences all number
    16
    0
    Dysphagia
         subjects affected / exposed
    14 / 181 (7.73%)
    0 / 27 (0.00%)
         occurrences all number
    16
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    11 / 181 (6.08%)
    0 / 27 (0.00%)
         occurrences all number
    14
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Micturition urgency
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    28 / 181 (15.47%)
    4 / 27 (14.81%)
         occurrences all number
    51
    4
    Alopecia
         subjects affected / exposed
    57 / 181 (31.49%)
    2 / 27 (7.41%)
         occurrences all number
    58
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Dermatitis bullous
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    39 / 181 (21.55%)
    2 / 27 (7.41%)
         occurrences all number
    42
    2
    Hyperkeratosis
         subjects affected / exposed
    58 / 181 (32.04%)
    4 / 27 (14.81%)
         occurrences all number
    102
    9
    Erythema
         subjects affected / exposed
    24 / 181 (13.26%)
    7 / 27 (25.93%)
         occurrences all number
    34
    11
    Pruritus
         subjects affected / exposed
    42 / 181 (23.20%)
    5 / 27 (18.52%)
         occurrences all number
    47
    5
    Photosensitivity reaction
         subjects affected / exposed
    39 / 181 (21.55%)
    5 / 27 (18.52%)
         occurrences all number
    44
    5
    Rash
         subjects affected / exposed
    44 / 181 (24.31%)
    10 / 27 (37.04%)
         occurrences all number
    60
    16
    Rash generalised
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    42 / 181 (23.20%)
    3 / 27 (11.11%)
         occurrences all number
    59
    5
    Skin fissures
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Toxic skin eruption
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Dermal cyst
         subjects affected / exposed
    18 / 181 (9.94%)
    0 / 27 (0.00%)
         occurrences all number
    24
    0
    Dermatitis
         subjects affected / exposed
    10 / 181 (5.52%)
    0 / 27 (0.00%)
         occurrences all number
    10
    0
    Keratosis pilaris
         subjects affected / exposed
    33 / 181 (18.23%)
    0 / 27 (0.00%)
         occurrences all number
    33
    0
    Milia
         subjects affected / exposed
    16 / 181 (8.84%)
    0 / 27 (0.00%)
         occurrences all number
    18
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    48 / 181 (26.52%)
    0 / 27 (0.00%)
         occurrences all number
    57
    0
    Papule
         subjects affected / exposed
    13 / 181 (7.18%)
    0 / 27 (0.00%)
         occurrences all number
    18
    0
    Rash papular
         subjects affected / exposed
    21 / 181 (11.60%)
    0 / 27 (0.00%)
         occurrences all number
    26
    0
    Skin lesion
         subjects affected / exposed
    11 / 181 (6.08%)
    0 / 27 (0.00%)
         occurrences all number
    18
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    79 / 181 (43.65%)
    14 / 27 (51.85%)
         occurrences all number
    123
    21
    Back pain
         subjects affected / exposed
    18 / 181 (9.94%)
    4 / 27 (14.81%)
         occurrences all number
    21
    4
    Muscle spasms
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Myalgia
         subjects affected / exposed
    18 / 181 (9.94%)
    3 / 27 (11.11%)
         occurrences all number
    23
    4
    Pain in extremity
         subjects affected / exposed
    13 / 181 (7.18%)
    2 / 27 (7.41%)
         occurrences all number
    14
    5
    Musculoskeletal pain
         subjects affected / exposed
    14 / 181 (7.73%)
    0 / 27 (0.00%)
         occurrences all number
    15
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    50 / 181 (27.62%)
    10 / 27 (37.04%)
         occurrences all number
    56
    15
    Dehydration
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    18 / 181 (9.94%)
    5 / 27 (18.52%)
         occurrences all number
    20
    7
    Hyponatraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    4
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    Folliculitis
         subjects affected / exposed
    18 / 181 (9.94%)
    3 / 27 (11.11%)
         occurrences all number
    24
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Rash pustular
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    3
    Skin infection
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 181 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2012
    Cohort 3 was split into two – the pre-existing Cohort 3a - vemurafenib only, and a new Cohort 3b - combination therapy with vemurafenib and cetuximab. The protocol was amended to include rationale for vemurafenib and cetuximab treatment in this cohort.
    18 Mar 2014
    Additional subjects (up to 70 subjects in total) were allowed to be recruited into a study cohort if a promising response rate was demonstrated in Stage II of that cohort. The exploratory objectives for the study were revised.
    16 Jan 2015
    The secondary objectives were changed to include the evaluation of tumor assessment scans by an independent review committee (IRC) for Cohort 1 (NSCLC) and other cohorts that demonstrate clinically meaningful efficacy per investigator assessment. The presence of BRAF V600 mutations could be retrospectively confirmed. Inclusion criteria for all subjects were changed to include male or female >/=16 years of age. Inclusion criteria for solid tumors and multiple myeloma were changed so that in order for the subject to be eligible, they must be able to provide a tumor sample (preferably tissue; alternatively DNA) for retrospective confirmation of the BRAF mutation by a central laboratory. IRC assessment of response rates was added a secondary efficacy endpoint focusing on Week 8, Week 16 and BOR for Cohort 1 (NSCLC) and other cohorts that demonstrate clinically meaningful efficacy per investigator assessment.
    24 Mar 2016
    Prior to the closure of the trial or should the study be closed due to Sponsor decision, it was added that the Sponsor may offer subjects who have completed the protocol-mandated minimum 12-month safety follow-up and who continue to benefit from vemurafenib therapy, the opportunity to receive continued vemurafenib via enrollment in the GO28399 extension trial. The interim analysis was changed to add efficacy analysis at 9 months for expanded cohorts. In case a cohort/indication is expanded up to 70 subjects, the primary analysis for efficacy will occur once all subjects have been followed up for 9 months after last subject had been enrolled in that cohort, or the subject develops progressive disease, withdraws consent, or is lost to follow-up, whichever occurred first.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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