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)

• ClinicalTrials.gov Identifier: NCT02576990
• Recruitment Status: Completed
• First Posted: October 15, 2015
• Results First Posted: June 24, 2020
• Last Update Posted: July 27, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: October 14, 2015
• First Posted Date: October 15, 2015
• Results First Submitted Date: May 26, 2020
• Results First Posted Date: June 24, 2020
• Last Update Posted Date: July 27, 2023
• Actual Study Start Date: December 2, 2015
• Actual Primary Completion Date: May 28, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2021)

Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria Per Independent Central Review [ Time Frame: Up to approximately 27 months (Database Cutoff: 28MAY2019) ]

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.

• Original Primary Outcome Measures (submitted: October 14, 2015): Overall Response Rate (ORR) by Independent Central Review [ Time Frame: Every 12 weeks for up to 2 years ]

Current Secondary Outcome Measures (submitted: September 21, 2021)

• ORR Based on IWG Response Assessment Criteria by Investigator Assessment [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Independent Central Review [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Duration of Response (DOR) Based on IWG Response Assessment Criteria by Independent Central Review in Participants With Responses [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants With Responses [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Independent Central Review [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.
• Overall Survival (OS) [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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).
• Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 30 months (Up to 90 days after last dose of study treatment) (Database Cutoff Date: 28MAY2019) ]
  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.
• Number of Participants Who Discontinued Study Drug Due to an AE [ Time Frame: Up to approximately 27 months (Database Cutoff Date: 28MAY2019) ]
  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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)

Brief Summary

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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Mediastinal Large B-cell Lymphoma
• Richter Syndrome

Intervention

Biological: Pembrolizumab

IV infusion

Other Names:

• MK-3475
• KEYTRUDA®
• SCH 900475

Study Arms

• Experimental: Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)
  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).
  Intervention: Biological: Pembrolizumab
• Experimental: Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
  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.
  Intervention: Biological: Pembrolizumab

Publications *

• Armand P, Rodig S, Melnichenko V, Thieblemont C, Bouabdallah K, Tumyan G, Ozcan M, Portino S, Fogliatto L, Caballero MD, Walewski J, Gulbas Z, Ribrag V, Christian B, Perini GF, Salles G, Svoboda J, Zain J, Patel S, Chen PH, Ligon AH, Ouyang J, Neuberg D, Redd R, Chatterjee A, Balakumaran A, Orlowski R, Shipp M, Zinzani PL. Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma. J Clin Oncol. 2019 Dec 1;37(34):3291-3299. doi: 10.1200/JCO.19.01389. Epub 2019 Oct 14.
• Armand P, Murawski N, Molin D, Zain J, Eichhorst B, Gulbas Z, Hawkes EA, Pagel JM, Phillips T, Ribrag V, Svoboda J, Stathis A, Chatterjee A, Orlowski R, Marinello P, Christian B. Pembrolizumab in relapsed or refractory Richter syndrome. Br J Haematol. 2020 Jul;190(2):e117-e120. doi: 10.1111/bjh.16762. Epub 2020 Jun 16. No abstract available.
• Zinzani PL, Thieblemont C, Melnichenko V, Bouabdallah K, Walewski J, Majlis A, Fogliatto L, Garcia-Sancho AM, Christian B, Gulbas Z, Ozcan M, Perini GF, Ghesquieres H, Shipp MA, Thompson S, Chakraborty S, Marinello P, Armand P. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170. Blood. 2023 Jul 13;142(2):141-145. doi: 10.1182/blood.2022019340.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 15, 2017): 80
• Original Estimated Enrollment (submitted: October 14, 2015): 53
• Actual Study Completion Date: October 23, 2020
• Actual Primary Completion Date: May 28, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Brazil, Chile, Colombia, France, Germany, Italy, Poland, Russian Federation, Spain, Sweden, Switzerland, Turkey, United States

Administrative Information

• NCT Number: NCT02576990
• Other Study ID Numbers: 3475-170; MK-3475-170 ( Other Identifier: Merck ); KEYNOTE-170 ( Other Identifier: Merck ); 2015-002406-37 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: July 2023