Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma or Relapsed or Refractory Richter Syndrome (MK-3475-170/KEYNOTE-170)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Mediastinal Large B-cell Lymphoma, Richter Syndrome

Intervention / Treatment
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* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary mediastinal large B-cell lymphoma (PMBCL): Diagnosis of relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) AND Has relapsed after autologous stem cell transplant (auto-SCT) or has failed to achieve a Complete Response or Partial Response within 60 days of auto-SCT. Participants may have received intervening therapy after auto-SCT for relapsed or refractory disease, in which case they must have relapsed after or be refractory to their last treatment OR For participants who are ineligible for auto-SCT, has received at least ≥2 lines of prior therapy and has failed to respond to or relapsed after their last line of treatment. For participants who received consolidative local radiotherapy after systemic therapy, local radiotherapy will not be considered as a separate line of treatment Previously exposed to rituximab as part of prior lines of treatment Richter syndrome (RS): Pathologic diagnosis per local institutional review of RS that transformed from chronic lymphocytic leukemia (CLL) Relapsed or refractory Richter syndrome and has received ≥1 previous treatment for RS All Participants: Radiographically measurable disease Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale Life expectancy >3 months Adequate organ function Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug Exclusion Criteria: Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug Is receiving systemic steroid therapy <3 days before the first dose of study drug or receiving any other form of immunosuppressive medication Prior monoclonal antibody within 4 weeks prior to study Day 1 (2 weeks for RS participants) or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier (2 weeks for RS participants) Prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or prior radiation therapy within 4 weeks prior to study Day 1 Allogeneic hematopoietic stem cell transplantation within the last 5 years. Has a known additional malignancy (except underlying CLL for RS) that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy Known clinically active central nervous system involvement Active autoimmune disease requiring systemic treatment in past 2 years History of (non-infectious) pneumonitis that required steroids, or current pneumonitis Active infection requiring intravenous systemic therapy Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study drug Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) Known human immunodeficiency virus (HIV), or Hepatitis B or C Has received a live vaccine within 30 days prior to first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)<br>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<br>* IV infusion<br>* Other names: SCH 900475;|
| Experimental: Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)<br>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<br>* IV infusion<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to approximately 27 months (Database Cutoff: 28MAY2019) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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. | Up to approximately 27 months (Database Cutoff Date: 28MAY2019) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death 1 (PD-1, PD1), Programmed Cell Death-Ligand 1 (PD-L1, PDL1), Programmed Cell Death-Ligand 2 (PD-L2, PDL2)