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    Clinical Trial Results:
    An international, randomized, open-label Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog pathway

    Summary
    EudraCT number
    		 2011-003372-37
    Trial protocol
    		 FR  
    Global end of trial date
    04 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Mar 2021
    First version publication date
    25 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET11-072
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01601184
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Léon Bérard
    Sponsor organisation address
    28 rue Laennec, LYON, France, 69008
    Public contact
    Dr Didier FRAPPAZ, Centre Léon Bérard, 33 4 78 78 28 28, DRCIreglementaire@lyon.unicancer.fr
    Scientific contact
    Dr Didier FRAPPAZ, Centre Léon Bérard, 33 4 78 78 28 28, DRCIreglementaire@lyon.unicancer.fr
    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
    06 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase I: to evaluate the safety of a fixed dose of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma Phase II: to estimate the efficacy of vismodegib in combination with concomitant temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma
    Protection of trial subjects
    At pre-registration visit, the investigator or its designee will inform the patient of the study, check the eligibility criteria using medical records of the patient and ask him/her to sign the Inform Consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 At pre-registration visit, the investigator or its designee will inform the patient of the study, check the eligibility criteria using medical records of the patient and ask him/her to sign the Inform Consent form.

    Pre-assignment
    Screening details
    		 Before randomisation, FFPE archival tumor samples will be collected for pathological review and assessment of SHH pathway activation by imunohistochemistry (SFRP1, Gab1, Filamin A, YAP1, b-catenin). Only patients with confirmed medulloblastoma presenting an activation of the SHH pathway validated by IHC will be randomized.

    Period 1
    Period 1 title
    Phase I
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 The combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles, n= 6 patients)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    Dose: 150mg/day continuously

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles

    Arm title
    		 Arm B
    Arm description
    		 Temozolomide alone (150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles

    Number of subjects in period 1 [1]
    		Arm A Arm B
    Started
    10
    5
    Completed
    10
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of successes expected to go further was not reached.
    Period 2
    Period 2 title
    Phase II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 The combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles, n= 6 patients)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    Dose: 150mg/day continuously

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles

    Arm title
    		 Arm B
    Arm description
    		 Temozolomide alone (150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles

    Number of subjects in period 2
    		Arm A Arm B
    Started
    10
    5
    Completed
    10
    5
    Period 3
    Period 3 title
    Compassionate period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Compassionate arm
    Arm description
    		 -
    Arm type
    		 compassionate arm

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Buccal use
    Dosage and administration details
    150 mg/day continuously

    Number of subjects in period 3 [2]
    		Compassionate arm
    Started
    9
    Completed
    9
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of successes expected to go further was not reached.

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 The combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles, n= 6 patients)

    Reporting group title
    Arm B
    Reporting group description
    		 Temozolomide alone (150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles
    Reporting group title
    Arm A
    Reporting group description
    		 The combination of vismodegib (150 mg/day continuously) with temozolomide (150 mg/m2 from day 1 to day 5 over a 28 day-cycle period during Cycle 1 and 200mg/m2 from day 1 to day 5 over a 28 day-cycle period during subsequent cycles, n= 6 patients)

    Reporting group title
    Arm B
    Reporting group description
    		 Temozolomide alone (150 mg/m2 day 1 to day 5 / 28 day-cycle during Cycle 1 and 200mg/m2 day 1 to day 5/ 28 day-cycle during subsequent cycles
    Reporting group title
    Compassionate arm
    Reporting group description
    		 -

    Primary: Primary end point

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    End point title
    		 Primary end point [1]
    End point description
    PHASE I: To evaluate the safety of a fixed dose of vismodegib in combination with temozolomide (TMZ) in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma measured by the incidence of adverse events graded using CTC AE v4.03 PHASE II: To estimate the efficacy of vismodegib in combination with concomitant temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma measured by the 6-month progression-free rate (Complete response + Partial Response + Stable disease according to WHO criteria
    End point type
    Primary
    End point timeframe
    PHASE II: 6 month
    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: Phase I: The safety profile of will be summarized with descriptive statistics (appropriate proportions with their 95% confidence interval). Phase II: The non progression rate at 6 months will be analyzed using central read tumor assessments. It will be summarized by a proportion together with its 95% confidence interval.
    End point values
    		 Arm A Arm B Arm A Arm B Compassionate arm
    Number of subjects analysed
    10
    5
    10
    5
    9
    Units: number of AE
    10
    5
    10
    5
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The investigator collects (spontaneous patient report or questionning) and immediately notifies the sponsor of all SAEs, in a written report, wether or not theay are deemed to be attributable to research and wich occur during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: At least one AE related to TMZ: 15 At least one AE related to vismodegib: 15 At least one AE related to TMZ and vismodegib: 9 At least one grade >=3 AE: 10 At least one SAE: 6 At least SAE related to TMZ: 1 At least one SAE related to vismodegib: 1 At least one SAE related to TMZ and vismodegib: 0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jun 2012
    Addition of a compassionate program for patients randomized to the "standard treatment" arm
    17 May 2013
    Authorize the inclusion of patients previously treated with temozolomide in a new treatment arm: Arm C = vismodegib alone (150 mg / d continuously) Update of clinical data implemented in the attached documents following the publication by Roche laboratories of a new BI for vismodegib
    04 Aug 2014
    Alignment of study documents with the SPC of vismodegib Modification of criterion I12 relating to the duration of contraception Update of the potential risks associated with ME in the benefit / risk balance Modification of the contraceptive methods accepted by the protocol Update of clinical data following the BI update
    22 Mar 2016
    Extend the duration of the inclusion period by 24 months and therefore the duration of the study
    27 Apr 2017
    New edition of the vismodegib BI (Version 10 of January 2016) Update of definitions and vigilance rules

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Mar 2019
    The number of successes expected to go further was not reached.
    -

    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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