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    Clinical Trial Results:
    A randomized phase II pilot study to evaluate safety and efficacy of the addition of vismodegib to standard neoadjuvant chemotherapy in triple negative breast cancer patients.

    Summary
    EudraCT number
    		 2014-001287-35
    Trial protocol
    		 ES  
    Global end of trial date
    13 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Sep 2021
    First version publication date
    24 Sep 2021
    Other versions
    Summary report(s)
    		 SPANISH REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    SHH-CM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02694224
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clínica Universidad de Navarra
    Sponsor organisation address
    Avda. Pío XII,36, Pamplona, Spain, 31008
    Public contact
    UCICEC, Clinica Universidad de Navarra, 34 948 25 54 00 1144, ucicec@unav.es
    Scientific contact
    UCICEC, Clinica Universidad de Navarra, 34 948 25 54 00 1144, ucicec@unav.es
    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 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety and efficacy of vismodegib with standard neoadjuvant chemotherapy in breast cancer patients based on the CTCAE v4 2010 scale.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    25
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Woman between 18 and 75 years.

    Pre-assignment
    Screening details
    		 Patients diagnosed with breast cancer (stages I-III) with triple negative subtype, who have not previously received chemotherapy or systemic therapy. In these patients, treatment with neoadjuvant chemotherapy established in the protocol is indicated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental group
    Arm description
    		 19 patients were randomized, of whom 18 completed the treatment phase. These patients were administered the usual neoadjuvant treatment of Paclitaxel, sequenced to epirubicin and cyclophosphamide in combination with Vismodegib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Erivedge
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg/day orally during the paclitaxel stage. Vismodegib will be administered daily for 12 weeks (84 days), coinciding with the duration of paclitaxel treatment (21-day cycles, with administration on days 1, 8 and 15 of the cycle, 12 administrations).

    Arm title
    		 Control group
    Arm description
    		 10 patients were randomized, of whom 9 completed the treatment. These patients are given neoadjuvant treatment of paclitaxel sequenced to epirubicin plus cyclophosphamide. Two to three weeks would pass between the last cycle of paclitaxel and the start of anthracyclines.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Weekly administration at a dose of 80 mg/m2 intravenously on days 1, 8 and 15 of each 21-day cycle (for 12 weeks).

    Investigational medicinal product name
    Epirubicina
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Intravenous route at a dose of 90 mg/m2. A total of 4 doses will be received every 2 weeks with granulocyte and monocyte factor support. Administered in combination with cyclophosphamide to all randomized patients.

    Investigational medicinal product name
    Ciclofosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Intravenous route at a dose of 600 mg/m2. A total of 4 doses will be received every 2 weeks with granulocyte and monocyte factor support. It is administered in combination with epirubicin to all randomized patients.

    Number of subjects in period 1
    		Experimental group Control group
    Started
    19
    9
    Completed
    18
    9
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 19 patients were randomized, of whom 18 completed the treatment phase. These patients were administered the usual neoadjuvant treatment of Paclitaxel, sequenced to epirubicin and cyclophosphamide in combination with Vismodegib.

    Reporting group title
    Control group
    Reporting group description
    		 10 patients were randomized, of whom 9 completed the treatment. These patients are given neoadjuvant treatment of paclitaxel sequenced to epirubicin plus cyclophosphamide. Two to three weeks would pass between the last cycle of paclitaxel and the start of anthracyclines.

    Reporting group values
    		 Experimental group Control group Total
    Number of subjects
    		 19 9 28
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.6 ( 9.3 ) 49.1 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 9 28
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 19 patients were randomized, of whom 18 completed the treatment phase. These patients were administered the usual neoadjuvant treatment of Paclitaxel, sequenced to epirubicin and cyclophosphamide in combination with Vismodegib.

    Reporting group title
    Control group
    Reporting group description
    		 10 patients were randomized, of whom 9 completed the treatment. These patients are given neoadjuvant treatment of paclitaxel sequenced to epirubicin plus cyclophosphamide. Two to three weeks would pass between the last cycle of paclitaxel and the start of anthracyclines.

    Primary: Safety and efficacy

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    End point title
    		 Safety and efficacy
    End point description
    Efficacy is analyzed by pathological complete response (pCR), which is determined by Miller & Paine calssification evaluated after surgery. In the control group 67% of patients were found to have a pCR, while in the experimental group 56% of patients obtained pCR. Fisher's exact test was used to determine a possible relationship between the group and having pCR or not. A p-value = 0.69 was obtained, which is not significant, so there is no statistical evidence to affirm that there are differences between the two variables.
    End point type
    Primary
    End point timeframe
    Markers of safety ans efficacy will be collected whith each systemic therapy. Toxicity will be evaluated based on CTCAE v4 2010 scale.
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    18
    9
    Units: patients
    number (confidence interval 95%)
        Pathological complete response (pCR)
    0.53 (0.36 to 0.84)
    0.67 (0.31 to 0.91)
    Statistical analysis title
    		 Relationship between groups
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The description of AEs was coded using the PT and SOC level of the MedDRA medical dictionary version 22.0.
    Adverse event reporting additional description
    The CRF records the description, start date, end date, intensity, relationship with treatment, expected, evolution, action taken and whether the adverse events are serious or not.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 19 (26.32%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gatrointestinal disorders
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (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: 1%
    Non-serious adverse events
    		 Experimental group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    4 / 19 (21.05%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    17 / 19 (89.47%)
    8 / 9 (88.89%)
         occurrences all number
    17
    8
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    7 / 19 (36.84%)
    4 / 9 (44.44%)
         occurrences all number
    7
    4
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    4 / 19 (21.05%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    15 / 19 (78.95%)
    6 / 9 (66.67%)
         occurrences all number
    15
    6
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    5 / 19 (26.32%)
    6 / 9 (66.67%)
         occurrences all number
    5
    6
    Eye disorders
    Eye disorders
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    14 / 19 (73.68%)
    8 / 9 (88.89%)
         occurrences all number
    14
    8
    Skin and subcutaneous tissue disorders
    Skin and subcutaneus tissue disorders
         subjects affected / exposed
    16 / 19 (84.21%)
    8 / 9 (88.89%)
         occurrences all number
    16
    8
    Hyperpigmentation
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    12 / 19 (63.16%)
    2 / 9 (22.22%)
         occurrences all number
    12
    2
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    4 / 19 (21.05%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    5 / 19 (26.32%)
    3 / 9 (33.33%)
         occurrences all number
    5
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2016
    new protocol version, Version 3
    21 Sep 2016
    new protocol version. Version 4

    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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