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    Clinical Trial Results:
    CHEMOIMMUNE - A Phase II study evaluating an anti-PD1 monoclonal antibody (pembrolizumab) in lymphopenic metastatic breast cancer patients treated with metronomic cyclophosphamide

    Summary
    EudraCT number
    		 2016-002736-33
    Trial protocol
    		 FR  
    Global end of trial date
    18 Sep 2019

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ET16-073
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03139851
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Léon Bérard
    Sponsor organisation address
    28 rue Laennec, LYON, France, 69008
    Public contact
    Dr O. TREDAN, Centre Léon Bérard, 33 4 78 78 28 28, DRCIreglementaire@lyon.unicancer.fr
    Scientific contact
    Dr O. TREDAN, 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
    16 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -Safety run-in phase: To evaluate the safety of a combination therapy using pembrolizumab in association with metronomic cyclophosphamide. -Phase II: To demonstrate the efficacy of a combined treatment associating pembrolizumab with metronomic cyclophosphamide in terms of 24-week Clinical Benefit Rate (CBR24w) as per RECIST 1.1.
    Protection of trial subjects
    Study treatments will continue to be administered as long as patient experiences clinical benefit in the opinion of the investigator or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent. The investigator will have to inform the patient of the study treatment, the objectives and the design of the study, as well as the biological samples collection, provide the patient information leaflet / Informed consent form, answer to any questions that the patient may have and ensure that she understands the potential risks and benefits of participating in the study before signing the informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2017
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At screening, a complete physical examination should be performed as per institutional practice with a measure of weight. During the study, a limited, symptom-oriented physical examinations should be performed. PS will be measured using the ECOG Scale. Vitals signs to be recorded include blood pressure, temperature, respiratory rate and pulse rate.

    Period 1
    Period 1 title
    Safety run-in phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 safety run-in phase
    Arm description
    		 A safety run-in phase aiming to evaluate the safety of the combination therapy pembrolizumab + metronomic cyclophosphamide based on the occurrence of severe toxicities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive cyclophosphamide (50 mg/day, daily, per os) and pembrolizumab (200 mg every 3 weeks, intravenously [IV]). A cycle is defined as an interval of 21 days.

    Number of subjects in period 1
    		safety run-in phase
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Two-stage phase II
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Two-stage phase II
    Arm description
    		 A two-stage phase II aiming to evaluate the clinical activity of the combination therapy pembrolizumab + metronomic cyclophosphamide. The first 6 patients enrolled in the safety run-in phase will be part of the Phase II analysis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive cyclophosphamide (50 mg/day, daily, per os) and pembrolizumab (200 mg every 3 weeks, intravenously [IV]). A cycle is defined as an interval of 21 days.

    Number of subjects in period 2
    		Two-stage phase II
    Started
    20
    Completed
    20

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    safety run-in phase
    Reporting group description
    		 A safety run-in phase aiming to evaluate the safety of the combination therapy pembrolizumab + metronomic cyclophosphamide based on the occurrence of severe toxicities.
    Reporting group title
    Two-stage phase II
    Reporting group description
    		 A two-stage phase II aiming to evaluate the clinical activity of the combination therapy pembrolizumab + metronomic cyclophosphamide. The first 6 patients enrolled in the safety run-in phase will be part of the Phase II analysis.

    Primary: Primary end point

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    End point title
    		 Primary end point [1]
    End point description
    End point type
    Primary
    End point timeframe
    Safety run-in phase To evaluate the safety of a combination therapy using pembrolizumab in association with metronomic cyclophosphamide. Phase II To demonstrate the efficacy of a combined treatment associating pembrolizumab with metronomic cyclophospha
    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: The analysis of the safety run-in phase will be performed after 6 weeks of follow-up of the first 6th patients. Phase II: At the end of Stage INB, an interim efficacy analysis will be performed with analysis of data from the first 18 evaluable patients.
    End point values
    		 safety run-in phase Two-stage phase II
    Number of subjects analysed
    6
    20
    Units: number toxicity
    6
    20
    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: 5%
    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: All patients experienced at least one AE: 14 patients (70%) had at least one event related to Pembrolizumab, and 16 patients (80%) had at least one event related to Cyclophosphamide. 12 patients experienced at least one AE grade ≥3, 15% of patients had at least one AE grade ≥3 related to Pembrolizumab, 40% of patients had at least one AE grade ≥3 related to Cyclophosphamide. No Immune related AE (irAE) was reported. No toxic death was reported.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2017
    Update of adverse events related to pembrolizumab (new AE including new irAE / imAE) Tumor biopsies : addition of criteria and precisions in order to perform tumor biopsies (to be performed as per investigator judgement , irradiated lesion should not be biopsied
    17 Jan 2018
    Update of dose modifications, supportive care in case of related AEs to pembrolizumab Addition of an exploratory objective: to explore the levels of TGFβ (bioactive and non-bioactive) in serum, plasma and platelets of breast cancer patients
    04 Jun 2018
    Modification of criteria I10 (ASAT and ALAT tolerated up to 5 ULN in case of liver metastases and suppression of LDH criteria)
    16 Jan 2019
    Update of adverse events related to pembrolizumab (new AE) Update of Data protection Section, following the General Data Protection Regulation (GDPR)
    18 Sep 2019
    Suppression of irRC criteria for endpoints of secondary objectives

    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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