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    Clinical Trial Results:
    A Phase II Study of Pembrolizumab (MK-3475) in Subjects with Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter Syndrome (rrRS)

    Summary
    EudraCT number
    		 2015-002406-37
    Trial protocol
    		 SE   PL   ES   FR  
    Global end of trial date
    23 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2021
    First version publication date
    07 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-170
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576990
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    23 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is being done to estimate the objective response rate (ORR) of pembrolizumab (MK-3475) by blinded independent central review (BICR) according to the International Working Group (IWG) response criteria, with special considerations for Richter Syndrome (RS) (relapsed or refractory RS (rrRS) participants only). The primary study hypothesis is that intravenous (IV) administration of single agent pembrolizumab to the relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) cohort will result in an Objective Response Rate (ORR) of greater than 15% using the International Working Group (IWG) response criteria (Cheson, 2007) by independent central review (ICR).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    80
    EEA total number of subjects
    38
    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)
    62
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the 80 participants allocated in the study, 76 participants received at least one dose of study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab: rrPMBCL
    Arm description
    		 Participants with rrPMBCL receive pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA® SCH 900475
    Pharmaceutical forms
    Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg of pembrolizumab Q3W, IV on Day 1 of each 3-week cycle for up to a maximum of 35 administrations (approximately 2 years).

    Arm title
    		 Pembrolizumab: rrRS
    Arm description
    		 Participants with rrRS receive pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475 KEYTRUDA® SCH 900475
    Pharmaceutical forms
    Powder for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg of pembrolizumab Q3W, IV on Day 1 of each 3-week cycle for up to a maximum of 35 administrations (approximately 2 years).

    Number of subjects in period 1
    		Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Started
    56
    24
    Treated
    53
    23
    Completed
    0
    0
    Not completed
    56
    24
         Adverse event, serious fatal
    29
    18
         Sponsor's decision
    24
    4
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    2
         Screen failure
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab: rrPMBCL
    Reporting group description
    		 Participants with rrPMBCL receive pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Reporting group title
    Pembrolizumab: rrRS
    Reporting group description
    		 Participants with rrRS receive pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Reporting group values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS Total
    Number of subjects
    		 56 24 80
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 35.0 ( 10.4 ) 67.2 ( 11.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 30 7 37
        Male
    		 26 17 43
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 51 24 75
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 0 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 1 5
        Not Hispanic or Latino
    		 37 21 58
        Unknown or Not Reported
    		 15 2 17

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab: rrPMBCL
    Reporting group description
    		 Participants with rrPMBCL receive pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Reporting group title
    Pembrolizumab: rrRS
    Reporting group description
    		 Participants with rrRS receive pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Primary: Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria per Independent Central Review (ICR)

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    End point title
    		 Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria per Independent Central Review (ICR) [1]
    End point description
    The ORR was assessed by ICR utilizing IWG response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as percentage of participants who had a response (complete response, CR or partial response, PR) prior to disease progression. CR is the disappearance of all evidence of disease & PR is the regression of measurable disease & no new sites. Participants with missing data were considered non-responders. In rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate. For rrPMBCL cohort, ORR was estimated and 95% 2-sided exact confidence interval (CI) using Clopper-Pearson method whereas rrRS cohort was estimated with 90% 2-sided CI. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Primary
    End point timeframe
    Up to approximately 27 months (Database Cutoff: 28MAY2019)
    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 comparisons were planned for this endpoint for database cutoff date 28May2019.
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Percentage of participants
        number (confidence interval 95%)
    45.3 (31.6 to 59.6)
    13.0 (3.7 to 30.4)
    No statistical analyses for this end point

    Secondary: ORR Based on IWG Response Assessment Criteria by Investigator Assessment

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    End point title
    		 ORR Based on IWG Response Assessment Criteria by Investigator Assessment
    End point description
    The ORR was assessed by Investigator assessment utilizing the IWG response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as the percentage of participants who had a response (CR or PR) prior to disease progression. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. Participants with missing data were considered non-responders. In the rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Percentage of participants
        number (confidence interval 90%)
    41.5 (30.0 to 53.7)
    4.3 (0.2 to 19.0)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by ICR

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    End point title
    		 Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by ICR
    End point description
    PFS was defined as the time from first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Months
        median (confidence interval 95%)
    5.5 (2.8 to 15.1)
    1.6 (1.0 to 2.1)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment

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    End point title
    		 Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment
    End point description
    PFS was defined as the time from the first dose to the first documented PD or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Months
        median (confidence interval 95%)
    4.3 (2.8 to 13.8)
    1.8 (1.0 to 2.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Based on IWG Response Assessment Criteria by ICR in Participants with Responses

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    End point title
    		 Duration of Response (DOR) Based on IWG Response Assessment Criteria by ICR in Participants with Responses
    End point description
    DOR was defined, only for subgroup of participants who achieved a CR or PR by ICR, as time from start of first documentation of objective tumor response (CR or PR) to first documentation of PD or death due to any cause, whichever comes first. CR is disappearance of all evidence of disease & PR is regression of measurable disease & no new sites. PD is appearance any new lesion or increase by ≥50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on date of last disease assessment documenting absence of PD for participants who did not have tumor progression & were still on study at time of an analysis, were given antitumor treatment other than study treatment, or were removed from study prior to documentation of tumor progression. 9999 indicates median or limit was not reached. The analysis population included all participants who received at least one dose of study drug & who achieved a CR or PR.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    24
    3
    Units: Months
        median (confidence interval 95%)
    9999 (25.2 to 9999)
    4.5 (2.7 to 6.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants with Responses

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    End point title
    		 Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants with Responses
    End point description
    DOR was defined, only for subgroup of participants who achieved a CR or PR by investigator assessment, as time from start of first documentation of objective tumor response (CR or PR) to first documentation of PD or death due to any cause, whichever comes first. CR is disappearance of all evidence of disease & PR is regression of measurable disease & no new sites. PD is appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on date of last disease assessment documenting absence of PD for participants who did not have tumor progression & were still on study at time of an analysis, were given antitumor treatment other than study treatment, or were removed from study prior to documentation of tumor progression. 9999 indicates median or limit was not reached. The analysis population included all participants who received at least one dose of study drug & who achieved a CR or PR.
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    24
    1
    Units: Months
        median (confidence interval 95%)
    9999 (25.2 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by ICR

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    End point title
    		 Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by ICR
    End point description
    DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or stable disease (SD) response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR or PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Percentage of participants
        number (confidence interval 90%)
    54.7 (42.6 to 66.5)
    17.4 (6.2 to 35.5)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment

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    End point title
    		 Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment
    End point description
    DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or SD response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR or PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Percentage of participants
        number (confidence interval 90%)
    52.8 (40.7 to 64.7)
    26.1 (12.0 to 45.1)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the first dose to death due to any cause. OS is presented from product limit (Kaplan-Meier) method for censored data (censored at the last assessment). 9999 indicates limit was not reached. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Months
        median (confidence interval 95%)
    22.3 (7.3 to 9999)
    3.8 (1.8 to 18.1)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who experienced an AE were reported. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 30 months (Up to 90 days after last dose of study treatment) (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Participants
    50
    23
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study drug due to an AE were reported. The analysis population included all participants who received at least one dose of study medication (pembrolizumab).
    End point type
    Secondary
    End point timeframe
    Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
    End point values
    		 Pembrolizumab: rrPMBCL Pembrolizumab: rrRS
    Number of subjects analysed
    53
    23
    Units: Participants
    6
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (AEs), non-serious AEs and all-cause mortality was collected up to approximately 56 months through end of trial (EOT) data cut-off date 23 Oct 2020.
    Adverse event reporting additional description
    All-cause mortality was reported on all allocated participants. Serious and non-serious AEs were reported among participants who received at least one dose of study treatment. MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study drug were excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Pembrolizumab: rrRS
    Reporting group description
    		 Participants with rrRS receive pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Reporting group title
    Pembrolizumab: rrPMBCL
    Reporting group description
    		 Participants with rrPMBCL receive pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).

    Serious adverse events
    		 Pembrolizumab: rrRS Pembrolizumab: rrPMBCL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 23 (65.22%)
    14 / 53 (26.42%)
         number of deaths (all causes)
    19
    30
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Cardiac tamponade
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Clostridium difficile infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab: rrRS Pembrolizumab: rrPMBCL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    46 / 53 (86.79%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    1 / 23 (4.35%)
    6 / 53 (11.32%)
         occurrences all number
    1
    11
    Hypoaesthesia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1
    Somnolence
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 53 (3.77%)
         occurrences all number
    2
    3
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 53 (7.55%)
         occurrences all number
    2
    5
    Anaemia
         subjects affected / exposed
    7 / 23 (30.43%)
    6 / 53 (11.32%)
         occurrences all number
    9
    6
    Lymph node pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 53 (3.77%)
         occurrences all number
    3
    3
    Neutropenia
         subjects affected / exposed
    2 / 23 (8.70%)
    15 / 53 (28.30%)
         occurrences all number
    2
    29
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    4
    Asthenia
         subjects affected / exposed
    2 / 23 (8.70%)
    7 / 53 (13.21%)
         occurrences all number
    2
    10
    Fatigue
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 53 (11.32%)
         occurrences all number
    8
    7
    Chills
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    3 / 23 (13.04%)
    15 / 53 (28.30%)
         occurrences all number
    4
    25
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 23 (13.04%)
    5 / 53 (9.43%)
         occurrences all number
    3
    5
    Constipation
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 53 (7.55%)
         occurrences all number
    3
    4
    Diarrhoea
         subjects affected / exposed
    5 / 23 (21.74%)
    7 / 53 (13.21%)
         occurrences all number
    5
    9
    Nausea
         subjects affected / exposed
    6 / 23 (26.09%)
    6 / 53 (11.32%)
         occurrences all number
    7
    8
    Stomatitis
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 53 (9.43%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 23 (8.70%)
    10 / 53 (18.87%)
         occurrences all number
    2
    11
    Cough
         subjects affected / exposed
    2 / 23 (8.70%)
    10 / 53 (18.87%)
         occurrences all number
    2
    15
    Oropharyngeal pain
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    4
    Productive cough
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Pruritus
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 53 (7.55%)
         occurrences all number
    1
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 23 (0.00%)
    6 / 53 (11.32%)
         occurrences all number
    0
    7
    Myalgia
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    4
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    5 / 53 (9.43%)
         occurrences all number
    2
    5
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Herpes zoster
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    8 / 53 (15.09%)
         occurrences all number
    0
    10
    Pharyngitis
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    5
    Rhinitis
         subjects affected / exposed
    0 / 23 (0.00%)
    5 / 53 (9.43%)
         occurrences all number
    0
    6
    Urinary tract infection
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Hyperglycaemia
         subjects affected / exposed
    4 / 23 (17.39%)
    4 / 53 (7.55%)
         occurrences all number
    4
    5
    Hyperkalaemia
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 53 (3.77%)
         occurrences all number
    2
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 53 (3.77%)
         occurrences all number
    2
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2016
    Major change of Amendment (AM) 1 included adding Richter syndrome cohort of participants.
    22 Feb 2017
    Major change of AM2 included adding inclusion criteria updates for future biomedical research and for Richter syndrome participants.
    02 Oct 2017
    Major changes of AM3 was to add interim analysis for rrPMBCL cohort of participants, adding formal hypothesis testing for primary objective and adding additional long term follow-up of participants who underwent allogenic stem cell transplant.
    18 Dec 2017
    Major change of AM4 was to expand the dose modification and toxicity management guidelines table to cover supportive care, monitoring, and follow up.
    20 Feb 2018
    Major change of AM5 was to add the efficacy update for participants with rrPMBCL to be conducted at 9 months after the last subject initiated treatment and 12 months after the last participant initiated treatment.
    07 Aug 2020
    Major change of AM6 was to allow ending of the trial.

    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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