A Phase 2 interventional study of Pembrolizumab in Mediastinal Large B-cell Lymphoma and Richter Syndrome, sponsored by Merck Sharp & Dohme LLC. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-07-27.
Sponsored by Merck Sharp & Dohme LLC · Phase 2, Interventional, and Treatment
In this study, participants with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) or relapsed or refractory Richter Syndrome (rrRS) will receive pembrolizumab (MK-3475). The efficacy of pembrolizumab in the treatment of rrPMBCL and rrRS will be evaluated. The primary study hypothesis is that intravenous (IV) administration of single agent pembrolizumab to the 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.
Effective with Protocol Amendment 04, enrollment into the rrRS cohort was closed.
Treatment with pembrolizumab will continue for a maximum of 35 administrations (approximately 2 years) or until documented disease progression by investigator assessment, unacceptable adverse event(s) (AEs), intercurrent illness that prevents further administration of treatment, participant withdraws consent, pregnancy of the participant, noncompliance with study treatment or procedure requirements, or administrative reasons.
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Exclusion Criteria:
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 a maximum of 35 administrations (approximately 2 years).
Biological: Pembrolizumab
Participants with rrRS receive pembrolizumab 200 mg Q3W, IV for each 3-week cycle for up to a maximum of 35 administrations (approximately 2 years). Effective with Protocol Amendment 04, enrollment into this cohort was closed.
Biological: Pembrolizumab
IV infusion
Also known as: MK-3475, KEYTRUDA®, SCH 900475
Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria Per Independent Central Review
The ORR was assessed by independent central review utilizing the International Working Group \[IWG\] 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 (complete response, CR or partial response, 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. For the rrPMBCL cohort, the ORR was estimated as well as a 95% 2-sided exact confidence interval (CI) using the Clopper-Pearson method whereas the rrRS cohort was estimated with a 90% 2-sided CI.
Time frame: Up to approximately 27 months (Database Cutoff: 28MAY2019)
ORR Based on IWG Response Assessment Criteria by Investigator Assessment
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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Independent Central Review
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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment
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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Duration of Response (DOR) Based on IWG Response Assessment Criteria by Independent Central Review in Participants With Responses
The DOR was defined, only for the subgroup of participants who achieved a CR or PR by independent central review, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the 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 the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants With Responses
The DOR was defined, only for the subgroup of participants who achieved a CR or PR by investigator assessment, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the 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 the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Independent Central Review
The 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/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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment
The 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/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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Overall Survival (OS)
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).
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
Number of Participants Who Experienced an Adverse Event (AE)
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.
Time frame: Up to approximately 30 months (Up to 90 days after last dose of study treatment) (Database Cutoff Date: 28MAY2019)
Number of Participants Who Discontinued Study Drug Due to an AE
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.
Time frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019)
| Milestone | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Started | 56 | 24 |
| Treated | 53 | 23 |
| Completed | 0 | 0 |
| Not completed | 56 | 24 |
| Withdrew: Death | 29 | 18 |
| Withdrew: Physician decision | 1 | 0 |
| Withdrew: Screen failure | 2 | 0 |
| Withdrew: Sponsor's decision | 24 | 4 |
| Withdrew: Withdrawal by subject | 0 | 2 |
The ORR was assessed by independent central review utilizing the International Working Group \[IWG\] 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 (complete response, CR or partial response, 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. For the rrPMBCL cohort, the ORR was estimated as well as a 95% 2-sided exact confidence interval (CI) using the Clopper-Pearson method whereas the rrRS cohort was estimated with a 90% 2-sided CI.
| Percentage of participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria Per Independent Central Review | 45.3 (31.6 to 59.6) | 13.0 (3.7 to 30.4) |
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.
| Percentage of participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| ORR Based on IWG Response Assessment Criteria by Investigator Assessment | 41.5 (30.0 to 53.7) | 4.3 (0.2 to 19.0) |
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.
| Months | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Independent Central Review | 5.5 (2.8 to 15.1) | 1.6 (1.0 to 2.1) |
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.
| Months | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment | 4.3 (2.8 to 13.8) | 1.8 (1.0 to 2.1) |
The DOR was defined, only for the subgroup of participants who achieved a CR or PR by independent central review, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the 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 the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
| Months | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Duration of Response (DOR) Based on IWG Response Assessment Criteria by Independent Central Review in Participants With Responses | NA (25.2 to NA) | 4.5 (2.7 to 6.2) |
The DOR was defined, only for the subgroup of participants who achieved a CR or PR by investigator assessment, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the 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 the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
| Months | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants With Responses | NA (25.2 to NA) | NA (NA to NA) |
The 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/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.
| Percentage of participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Independent Central Review | 54.7 (42.6 to 66.5) | 17.4 (6.2 to 35.5) |
The 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/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.
| Percentage of participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment | 52.8 (40.7 to 64.7) | 26.1 (12.0 to 45.1) |
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).
| Months | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Overall Survival (OS) | 22.3 (7.3 to NA) | 3.8 (1.8 to 18.1) |
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.
| Participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event (AE) | 50 | 23 |
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.
| Participants | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Number of Participants Who Discontinued Study Drug Due to an AE | 6 | 4 |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | 30/56 (53.6%) | 14/53 (26.4%) | 46/53 (86.8%) |
| Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) | 19/24 (79.2%) | 15/23 (65.2%) | 23/23 (100%) |
| Event | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 1/53 | 3/23 |
| HypercalcaemiaMetabolism and nutrition disorders | 0/53 | 2/23 |
| Autoimmune haemolytic anaemiaBlood and lymphatic system disorders | 0/53 | 1/23 |
| NeutropeniaBlood and lymphatic system disorders | 0/53 | 1/23 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/53 | 1/23 |
| Hypercalcaemia of malignancyEndocrine disorders | 0/53 | 1/23 |
| HyperthyroidismEndocrine disorders | 0/53 | 1/23 |
| DeathGeneral disorders | 0/53 | 1/23 |
| General physical health deteriorationGeneral disorders | 0/53 | 1/23 |
| CholecystitisHepatobiliary disorders | 0/53 | 1/23 |
| Event | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) |
|---|---|---|
| FatigueGeneral disorders | 6/53 | 8/23 |
| AnaemiaBlood and lymphatic system disorders | 6/53 | 7/23 |
| NeutropeniaBlood and lymphatic system disorders | 15/53 | 2/23 |
| PyrexiaGeneral disorders | 15/53 | 3/23 |
| NauseaGastrointestinal disorders | 6/53 | 6/23 |
| DiarrhoeaGastrointestinal disorders | 7/53 | 5/23 |
| CoughRespiratory, thoracic and mediastinal disorders | 10/53 | 2/23 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 10/53 | 2/23 |
| HyperglycaemiaMetabolism and nutrition disorders | 4/53 | 4/23 |
| NasopharyngitisInfections and infestations | 8/53 | 0/23 |
All allocated participants
| Age, Continuous(Years) | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) | Total |
|---|---|---|---|
| Mean | 35.0 ± 10.4 | 67.2 ± 11.0 | 44.7 ± 18.2 |
| Sex: Female, Male(Participants) | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) | Total |
|---|---|---|---|
| Female | 30 | 7 | 37 |
| Male | 26 | 17 | 43 |
| Ethnicity (NIH/OMB)(Participants) | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) | Total |
|---|---|---|---|
| Hispanic or Latino | 4 | 1 | 5 |
| Not Hispanic or Latino | 37 | 21 | 58 |
| Unknown or Not Reported | 15 | 2 | 17 |
| Race (NIH/OMB)(Participants) | Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) | Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) | Total |
|---|---|---|---|
| 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 |
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