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    Clinical Trial Results:
    Phase IIa trial of PD-L1 peptide vaccination as monotherapy in high risk smoldering multiple myeloma

    Summary
    EudraCT number
    		 2018-003990-93
    Trial protocol
    		 DK  
    Global end of trial date
    10 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Nov 2022
    First version publication date
    06 Nov 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MY18H2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03850522
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev Hospital
    Sponsor organisation address
    Borgmester Ib Juuls Vej 1, Herlev, Denmark, 2730
    Public contact
    Clinical Trial Information, Center for Cancer Immune Therapy, Department of Hematology, Herlev and Gentofte University Hospital, nicolai.groenne.dahlager.joergensen.01@regionh.dk
    Scientific contact
    Clinical Trial Information, Center for Cancer Immune Therapy, Department of Hematology, Herlev and Gentofte University Hospital, nicolai.groenne.dahlager.joergensen.01@regionh.dk
    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
    10 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the phase IIa trial is to investigate the rate of response in patients with high risk smoldering multiple myeloma vaccinated with PD-L1 long1. Furthermore, immunogenicity of the vaccine, adverse events, quality of life, time to progression and overall survival will be described. Hypothesis: Ten vaccinations with the peptide PD-L1 long1 will lead to a decline of 50% or more of the M-component or involved free light chain measured in the blood of patients with high risk smoldering multiple myeloma two weeks after last vaccination.
    Protection of trial subjects
    The patient will be observed for acute reactions for 15 minutes after the vaccination, where pulse and blood pressure will be measured prior to the vaccination and before the patient leaves the outpatient clinic. Pain during administration can be handled with mild analgesic such as 500-1000 mg paracetamol. If acute reactions occur, the patient will be treated according to guidelines and the patient will be excluded if the reaction is serious. Regarding exclusion due to acute reactions, vasovagal reactions are not considered as acute and must be ruled out. Safety will be evaluated on basis of symptoms reported by the participating patients as well as assessed with laboratory parameters from e.g. blood samples and ECG. Methods and timing for assessment, recording and analysis of safety parameters Adverse events will be recorded from first vaccination until the end-of-study visit two weeks after last the vaccine. In relation with each visit with vaccination, the patient will be questioned about new symptoms since last vaccination or changes in symptoms since last vaccination. If the patient has symptoms, the health professional responsible for the visit (whether it is a nurse trained for the study or a sub investigator) will record symptoms in the patient’s electronic health records and record adverse events according to CTCAE version 4.03 in the CTC-file. The questioning about symptoms can be performed at the physical visit or by telephone up to 48 hours before the vaccination. The vaccine will be given by a nurse trained for giving the vaccine in this trial or by a sub investigator or the primary investigator. The patients will be asked to complete the PRO-CTCAE questionnaire, specifically designed to capture symptomatic toxicities from the PD-L1 vaccines as experienced in the phase I study of the PD-L1 vaccine as well as literature review. Also, the PRO-CTCAE contains the possibility for patients themselves to describe any unexpected symptomatic toxicities
    Background therapy
    		 None Standard of care is observation.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Feb 2019
    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
    Denmark: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    3
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Since high risk smoldering multiple myeloma is a rare disease, enrollment of more than 10 patients can be challenged by incoming competing trials, the study will be closed after 1,5 years. Patients will be recruited from the departments of hematology in Denmark. Smoldering multiple myeloma and a maximum of 5 years after diagnosis.

    Pre-assignment
    Screening details
    		 29 patients were screened.

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

    Arms
    Arm title
    		 Vaccination
    Arm description
    		 500 μl aqueous solution of 100μg PD-L1 long1 peptide dissolved in DMSO and PBS is mixed to an emulsion with 500μl Montanide ISA-51, given subcutaneously every second week for a total of 10 vaccinations per patient. If the investigator deems that the patient is benefitting from vaccinations, the patient can continue in the extension phase of the study and receive up to 20 additional vaccinations. In the extension phase of the study, the frequency of vaccinations can be increased to weekly and several treatment pauses can be inserted.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IO103
    Investigational medicinal product code
    Other name
    PD-L1 long1
    Pharmaceutical forms
    Emulsion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The IO103 drug product is a freeze dried powder to be dissolved DMSO and in water for injection. The solution is administered subcutaneously after mixing with adjuvant (Montanide ISA 51 VG). A 500 μl aqueous solution of 100μg PD-L1 long1 peptide dissolved in DMSO and PBS is mixed to an emulsion with 500μl Montanide ISA-51 and given as a subcutaneous injection on the lateral side of the upper arm preceded by disinfection.

    Number of subjects in period 1
    		Vaccination
    Started
    6
    Completed
    5
    Not completed
    1
         Physician decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 6 6
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 3 3
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Vaccination
    Reporting group description
    		 500 μl aqueous solution of 100μg PD-L1 long1 peptide dissolved in DMSO and PBS is mixed to an emulsion with 500μl Montanide ISA-51, given subcutaneously every second week for a total of 10 vaccinations per patient. If the investigator deems that the patient is benefitting from vaccinations, the patient can continue in the extension phase of the study and receive up to 20 additional vaccinations. In the extension phase of the study, the frequency of vaccinations can be increased to weekly and several treatment pauses can be inserted.

    Primary: Overall response rate

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    End point title
    		 Overall response rate [1]
    End point description
    Patients with a response according to the IMWG criteria as PR+VGPR+CR+sCR during treatment and two weeks after end of treatment per patient.
    End point type
    Primary
    End point timeframe
    Planned analysis cut-off per patient: two weeks after last vaccination
    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: No statistical analyses were performed on this endpoint.
    End point values
    		 Vaccination
    Number of subjects analysed
    5
    Units: response
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until two weeks after last vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Vaccination
    Reporting group description
    		 500 μl aqueous solution of 100μg PD-L1 long1 peptide dissolved in DMSO and PBS is mixed to an emulsion with 500μl Montanide ISA-51, given subcutaneously every second week for a total of 10 vaccinations per patient. If the investigator deems that the patient is benefitting from vaccinations, the patient can continue in the extension phase of the study and receive up to 20 additional vaccinations. In the extension phase of the study, the frequency of vaccinations can be increased to weekly and several treatment pauses can be inserted.

    Serious adverse events
    		 Vaccination
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Vaccination
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Immune system disorders
    Flu-like symptoms after vaccination
    Additional description: One patient had grade 1 to 2 flu-like symptoms after most vaccinations.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    22
    Gastrointestinal disorders
    Bloating
    Additional description: Mild bloating and gastrointestinal dyscomfort. 1 patient, grade 2, 2 days. Known for the patient, not different from other frequent occurences for the patient previously.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Diverticulitis
    Additional description: 1 patient, grade 2, 16 days till last symptom. A known recurrent problem for the patient, not different from previous occurrences.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Sore throat
    Additional description: Grade 2 in one patient, lasted 2 days.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Injection site reaction
         subjects affected / exposed
    6 / 6 (100.00%)
         occurrences all number
    30
    Musculoskeletal and connective tissue disorders
    Bursitis
    Additional description: Bursitis olecrani, 1 patient, grade 2, lasted 5 days. Has had it previously.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    Viral infektion
    Additional description: Grade 2 viral infektion, one patient, lasting 2 days.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Otitis media
    Additional description: 1 patient, lasting 2 days, the patient is known with recurring otitis media, this occurence was no different than the cases the patient has had many times.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2019
    Possibility to extend the planned 10 vaccinations to an additional up to 20 vaccines in patients deemed to have effect of the vaccine.

    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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