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    Clinical Trial Results:
    A Pivotal Phase II, Multicenter, Single-arm, Two-cohort Trial Evaluating the Efficacy and Safety of GDC-0449 in Patients With Advanced Basal Cell Carcinoma

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    		 2008-004945-27
    Trial protocol
    		 BE   DE   GB  
    Global end of trial date
    09 Apr 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 May 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Quality check of data already entered before access for sponsors was blocked on 31 July 2015

    Trial information

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    Trial identification
    Sponsor protocol code
    SHH4476g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00833417
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Other study ID: GO01541
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, 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
    09 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a Phase II, single-arm, two-cohort multicenter clinical trial evaluating the efficacy and safety of vismodegib (GDC-0449) in subjects with advanced basal cell carcinoma (BCC). All subjects received vismodegib until evidence of progression, intolerable toxicities most probably attributable to vismodegib, or withdrawal from the study.
    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
    10 Feb 2009
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    United States: 72
    Worldwide total number of subjects
    104
    EEA total number of subjects
    30
    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)
    57
    From 65 to 84 years
    41
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study population consisted of subjects >= 18 years old with a histologically confirmed diagnosis of advanced basal cell carcinoma (BCC), either metastatic or locally advanced BCC. Enrollment of subjects with locally advanced BCC was limited to 80 of a planned total of 100 subjects. Both cohorts received the same vismodegib 150 mg treatment.

    Pre-assignment
    Screening details
    		 Subjects with metastatic BCC were required to have histologic confirmation of a distant BCC metastasis. Subjects with locally advanced BCC were required to have disease that was considered inoperable or to have a medical contraindication to surgery.

    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
    		 Metastatic Basal-Cell Carcinoma
    Arm description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vismodegib
    Investigational medicinal product code
    GDC-0449
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study

    Arm title
    		 Locally Advanced Basal-Cell Carcinoma
    Arm description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vismodegib
    Investigational medicinal product code
    GDC-0449
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study

    Number of subjects in period 1
    		Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma
    Started
    33
    71
    Completed
    0
    0
    Not completed
    33
    71
         Physician decision
    3
    7
         Sponsor decision to terminate study
    1
    2
         Disease progression
    18
    17
         Adverse event, non-fatal
    5
    16
         Death
    1
    3
         Lost to follow-up
    1
    2
         Patient decision to withdraw
    4
    23
         Reason not specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metastatic Basal-Cell Carcinoma
    Reporting group description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.

    Reporting group title
    Locally Advanced Basal-Cell Carcinoma
    Reporting group description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.

    Reporting group values
    		 Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma Total
    Number of subjects
    		 33 71 104
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 38 57
        From 65-84 years
    		 13 28 41
        85 years and over
    		 1 5 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ± 11.4 61.2 ± 16.8 -
    Gender categorical
    Units: Subjects
        Female
    		 9 32 41
        Male
    		 24 39 63
    Subject analysis sets

    Subject analysis set title
    Metastatic and Locally Advanced BCC Cohorts
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy-evaluable population: All treated patients for whom the independent pathologist's interpretation of archival tissue or baseline biopsies was consistent with basal cell carcinoma.

    Subject analysis sets values
    		 Metastatic and Locally Advanced BCC Cohorts
    Number of subjects
    104
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    57
        From 65-84 years
    41
        85 years and over
    6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.4 ± 15.2
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Metastatic Basal-Cell Carcinoma
    Reporting group description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.

    Reporting group title
    Locally Advanced Basal-Cell Carcinoma
    Reporting group description
    		 Subjects received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.

    Subject analysis set title
    Metastatic and Locally Advanced BCC Cohorts
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy-evaluable population: All treated patients for whom the independent pathologist's interpretation of archival tissue or baseline biopsies was consistent with basal cell carcinoma.

    Primary: Objective Response (OR) Determined by the Independent Review Facility

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    End point title
    		 Objective Response (OR) Determined by the Independent Review Facility [1]
    End point description
    OR=complete (CR) or partial response (PR). Metastatic-CR:Disappearance of all targets. PR:≥30% decreased sum of longest diameter (SLD) of targets compared to baseline (B). Locally advanced-Response=No progressive disease (PD) and ≥30% decreased SLD from baseline (radiography [R]) or ≥30% decreased SLD from B (externally visible dimension [EVD]) or completely resolved ulceration. CR:Response with no residual BCC on tumor biopsy (otherwise response was PR). PD:Any of ≥20% increased SLD from nadir (R or EVD), new ulceration, new lesions (R or physical exam) or non-target lesion progression by R.
    End point type
    Primary
    End point timeframe
    From study initiation (enrollment of first subject) through 9 months following the first treatment of the last enrolled subject (clinical cutoff date of 26 November 2010)
    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: Statistical analysis for clinical benefit was run against a pre-specified value for each cohort, not a comparison between groups, to exclude a response rate of <= 10% for Metastatic BCC cohort (n=33 in analysis) and <= 20% for the Locally Advanced BCC cohort (n=63 in analysis).
    End point values
    		 Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma
    Number of subjects analysed
    33
    63
    Units: Percentage of participants
        number (confidence interval 95%)
    30.3 (15.6 to 48.2)
    42.9 (30.5 to 56)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (OR) Determined by the Independent Review Facility

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    End point title
    		 Duration of Objective Response (OR) Determined by the Independent Review Facility
    End point description
    Duration of OR was defined as the time from the initial CR or PR to the earliest documented disease progression (PD) or death. Metastatic BCC - PD: ≥ 20% increased sum of the longest diameter (SLD) of targets from nadir, or 1 or more new lesions. Locally advanced BCC - PD: any of: (1) ≥ 20% increased SLD from nadir (radiography or externally visible dimension); (2) new ulceration; (3) new lesions (radiography or physical exam); (4) progression of non-target lesions by radiography.
    End point type
    Secondary
    End point timeframe
    From study initiation (enrollment of first subject) through 9 months following the first treatment of the last enrolled subject (clinical cutoff date of 26 November 2010)
    End point values
    		 Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma
    Number of subjects analysed
    10 [2]
    27
    Units: Months
        median (confidence interval 95%)
    7.6 (5.62 to 999)
    7.6 (5.65 to 9.66)
    Notes
    [2] - 999 = value not estimable
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Determined by the Independent Review Facility

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    End point title
    		 Progression-free Survival (PFS) Determined by the Independent Review Facility
    End point description
    PFS was defined as the time from start of treatment to the earliest documented disease progression (PD) or death. Metastatic BCC - PD: ≥ 20% increased sum of the longest diameter (SLD) of targets from nadir, or 1 or more new lesions. Locally advanced BCC - PD: any of: (1) ≥ 20% increased SLD from nadir (radiography or externally visible dimension); (2) new ulceration; (3) new lesions (radiography or physical exam); (4) progression of non-target lesions by radiography.
    End point type
    Secondary
    End point timeframe
    From study initiation (enrollment of first subject) through 9 months following the first treatment of the last enrolled subject (clinical cutoff date of 26 November 2010)
    End point values
    		 Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma
    Number of subjects analysed
    33 [3]
    63
    Units: Months
        median (confidence interval 95%)
    9.5 (7.36 to 999)
    9.5 (7.39 to 11.93)
    Notes
    [3] - 999 = value not estimable
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from the initial dose of vismodegib until death from any cause.
    End point type
    Secondary
    End point timeframe
    From study initiation (enrollment of first subject) through 9 months following the first treatment of the last enrolled subject (clinical cutoff date of 26 November 2010)
    End point values
    		 Metastatic Basal-Cell Carcinoma Locally Advanced Basal-Cell Carcinoma
    Number of subjects analysed
    33 [4]
    63
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Notes
    [4] - 999 = value not estimable
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 (SF-36) Health Survey Scores

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    End point title
    		 Change From Baseline in Short Form 36 (SF-36) Health Survey Scores
    End point description
    The SF-36 Health Survey (Version 2) uses patient-reported symptoms on 8 subscales to assess health-related quality of life (HRQoL). The Physical Component Summary (PCS) score summarizes the subscales Physical Functioning, Role−Physical, Bodily Pain, and General Health. The Mental Component Summary (MCS) score summarizes the subscales Vitality, Social Functioning, Role−Emotional, and Mental Health. Each score was scaled from 0 to 100. A positive change score indicates better HRQoL.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, and at the end of the study or early termination visit
    End point values
    		 Metastatic and Locally Advanced BCC Cohorts
    Number of subjects analysed
    93
    Units: Units on a scale
    arithmetic mean (confidence interval 95%)
        Change in MCS score at Week 12, n=82
    2.2 (-0.22 to 4.62)
        Change in MCS score at Week 24, n=75
    2.29 (0.05 to 4.53)
        Change in MCS score at end of study, n=20
    -3.8 (-10.55 to 2.96)
        Change in PCS score at Week 12, n=82
    -1.25 (-2.86 to 0.36)
        Change in PCS score at Week 24, n=75
    -1.9 (-3.75 to -0.05)
        Change in PCS score at end of study, n=20
    -2.86 (-7.39 to 1.66)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Absence of Residual Basal Cell Carcinoma BCC in Subjects With Locally Advanced BCC

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    End point title
    		 Number of Subjects With Absence of Residual Basal Cell Carcinoma BCC in Subjects With Locally Advanced BCC [5]
    End point description
    In subjects with locally advanced BCC, the histopathological effect of vismodegib was determined in tissue biopsies obtained at baseline and following vismodegib treatment. Reported is the number of subjects with pathology confirmed BCC in baseline biopsy, who had an absence of residual BCC post-baseline as assessed by an independent pathological review. This endpoint was measured in the efficacy-evaluable population: All treated subjects for whom the independent pathologist's interpretation of archival tissue or baseline biopsies was consistent with basal cell carcinoma. Only locally advanced BCC subjects with available post-baseline biopsy assessed by an independent pathologist were included in the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline through end of the study
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is specific to the arm labeled Locally Advanced BCC cohort. Therefore, data/statistics are not reported for the arm labeled Metastatic BCC cohort.
    End point values
    		 Locally Advanced Basal-Cell Carcinoma
    Number of subjects analysed
    51
    Units: Number of participants
    number (not applicable)
        Absence of Residual BCC
    34
        Prior to Week 24
    6
        At Week 24
    27
        After Week 24
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were recorded from study initiation (enrollment of first subject) through the end of the study (09 Apr 2014).
    Adverse event reporting additional description
    Adverse events were reported for the safety analysis population, which was defined as all enrolled subjects who received any amount of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    NA
    Reporting groups
    Reporting group title
    Metastatic and Locally Advanced BCC Cohorts
    Reporting group description
    		 Patients received vismodegib 150 mg orally once daily until disease progression; intolerable toxicity, most probably attributable to vismodegib; or withdrawal from the study.

    Serious adverse events
    		 Metastatic and Locally Advanced BCC Cohorts
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 104 (34.62%)
         number of deaths (all causes)
    35
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sarcoma
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac flutter
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsions local
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Aphagia
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Metastatic and Locally Advanced BCC Cohorts
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 104 (99.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    12 / 104 (11.54%)
         occurrences all number
    27
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    4
    Hypertension
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    3
    Hypotension
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 104 (9.62%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    45 / 104 (43.27%)
         occurrences all number
    58
    Influenza like illness
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    7
    Local swelling
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    7
    Oedema peripheral
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    7
    Pain
         subjects affected / exposed
    10 / 104 (9.62%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 104 (20.19%)
         occurrences all number
    23
    Dyspnoea
         subjects affected / exposed
    8 / 104 (7.69%)
         occurrences all number
    13
    Epistaxis
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    3
    Oropharyngeal pain
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    7
    Upper-airway cough syndrome
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    9
    Depression
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    13
    Insomnia
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    54 / 104 (51.92%)
         occurrences all number
    92
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    7
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    3
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    12 / 104 (11.54%)
         occurrences all number
    13
    Dizziness
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    12
    Dysgeusia
         subjects affected / exposed
    58 / 104 (55.77%)
         occurrences all number
    90
    Headache
         subjects affected / exposed
    16 / 104 (15.38%)
         occurrences all number
    24
    Hypoaesthesia
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    7
    Hypogeusia
         subjects affected / exposed
    11 / 104 (10.58%)
         occurrences all number
    12
    Paraesthesia
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    9
    Tremor
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 104 (7.69%)
         occurrences all number
    10
    Eye disorders
    Eye pain
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    18
    Constipation
         subjects affected / exposed
    20 / 104 (19.23%)
         occurrences all number
    25
    Diarrhoea
         subjects affected / exposed
    28 / 104 (26.92%)
         occurrences all number
    71
    Dyspepsia
         subjects affected / exposed
    11 / 104 (10.58%)
         occurrences all number
    14
    Flatulence
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    34 / 104 (32.69%)
         occurrences all number
    62
    Stomatitis
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    19 / 104 (18.27%)
         occurrences all number
    38
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    5
    Actinic keratosis
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    6
    Alopecia
         subjects affected / exposed
    69 / 104 (66.35%)
         occurrences all number
    86
    Erythema
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    4
    Hair growth abnormal
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    6
    Madarosis
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    5
    Night sweats
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    11 / 104 (10.58%)
         occurrences all number
    13
    Rash
         subjects affected / exposed
    8 / 104 (7.69%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 104 (14.42%)
         occurrences all number
    18
    Arthritis
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    8
    Bone pain
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    5
    Muscle spasms
         subjects affected / exposed
    75 / 104 (72.12%)
         occurrences all number
    179
    Muscular weakness
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    8
    Pain in extremity
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    9
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    3
    Conjunctivitis
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    10
    Eye infection
         subjects affected / exposed
    3 / 104 (2.88%)
         occurrences all number
    4
    Folliculitis
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    5
    Furuncle
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    4
    Infection
         subjects affected / exposed
    4 / 104 (3.85%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    14 / 104 (13.46%)
         occurrences all number
    16
    Oral candidiasis
         subjects affected / exposed
    2 / 104 (1.92%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 104 (8.65%)
         occurrences all number
    13
    Urinary tract infection
         subjects affected / exposed
    10 / 104 (9.62%)
         occurrences all number
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 104 (27.88%)
         occurrences all number
    47

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2008
    In the safety plan intolerable toxicities are defined as new (not present at baseline) Grade 3 or 4 adverse events considered related to GDC-0449 that are likely to be life-threatening or irreversible, and when in the opinion of the investigator, the risk outweighs the benefit of continued treatment with GDC-0449. Added to Exclusion Criteria: Subjects with superficial multifocal BCC who may be considered unresectable due to breadth of involvement. Added to Tumor Assessments during Treatment, End of Study, or Early Termination: If the investigator’s assessment of progressive disease is equivocal, and in the investigator’s opinion the subject is still deriving benefit from treatment, treatment with GDC-0449 should be continued, and the subject should be re-evaluated at the next tumor assessment time point.
    15 Jan 2010
    A requirement has been added for the investigator to consult the Medical Monitor before restarting GDC-0449 if a subject has experienced two treatment interruptions. In the eligibility criteria it has been clarified that for subjects with locally advanced BCC, the archival tissue submitted must be from a target lesion. It has been clarified that subjects with metastatic disease confined to bone are not considered eligible because of a lack of Response Evaluation Criteria In Solid Tumors (RECIST)-measurable disease, and that the Medical Monitor should be contacted if the investigator believes that a bone metastasis has an associated soft-tissue component that may be RECIST measurable. Inability or unwillingness to swallow capsules has been added as an exclusion criterion. Subjects who discontinue treatment with GDC-0449 but do not request withdrawal from the study will continue all study assessments. A requirement for a baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis has been added for subjects in the locally advanced cohort, to rule out occult metastatic disease or other preexisting radiographic abnormalities.
    14 Apr 2011
    The primary reason for the amendment is to provide safety updates. Specifically, the criteria for defining female subjects of childbearing and non-childbearing potential have been updated. The time period after which female subjects can become pregnant or plan to become pregnant following GDC-0449 treatment has been reduced from 12 months to 7 months. Sexually active male subjects must use a barrier form of contraception during GDC-0449 treatment and for 7 months after the last dose (previously 3 months) and should not donate sperm during this timeframe. In addition, the protocol now reflects the International Nonproprietary Name (INN) for GDC-0449: vismodegib. Language has been added to clarify that the study will continue after the completion of the planned analysis and that all subjects remaining on study will continue assessments and procedures according to the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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