A Trial of Pembrolizumab (MK-3475) in Participants With Blood Cancers (MK-3475-013/KEYNOTE-013)

NCT01953692 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 3475-0132013-001603-37MK-3475-013
• Study Type: interventional
• Target: 197
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this trial is to evaluate the safety, tolerability, and efficacy of pembrolizumab (MK-3475, KEYTRUDA®) and pembrolizumab in combination with lenalidomide (Cohort 5 only) in hematologic malignancies. The primary study hypotheses are that treatment with pembrolizumab will result in a clinically meaningful improvement in Objective Response Rate (ORR) or Complete Remission Rate (CRR). The study includes an initial dose determination to establish the recommended phase 2 dose (RP2D) of lenalidomide given in combination with pembrolizumab in Cohort 5. With Protocol Amendment 08, enrollment in the Multiple Myeloma arm (Cohort 2) has been completed and no further enrollment will be allowed and enrollment in the Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma arm (Cohort 5) has been discontinued and no further enrollment will be allowed.

Conditions

Myelodysplastic Syndrome; Multiple Myeloma; Hodgkin Lymphoma; Non-Hodgkin Lymphoma; Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Primary Mediastinal B-Cell Lymphoma

Keywords

PD1; PD-1; PDL1; PD-L1

Outcome Measures

Primary Outcomes (8)

• Number of Participants Who Experienced One or More Adverse Events (AEs):

  An adverse event was defined as any untoward medical occurrence in a participant administered study treatment and did not necessarily have a causal relationship with this treatment. An adverse event could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the study treatment was also an adverse event.

  Up to approximately 78.5 months

• Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

  An adverse event was defined as any untoward medical occurrence in a participant administered study treatment and did not necessarily have a causal relationship with this treatment. An adverse event could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the study treatment was also an adverse event.

  Up to approximately 78.5 months

• Objective Response Rate (ORR) in Cohort 1: Myelodysplastic Syndrome (MDS)

  ORR was defined as the percentage of participants with response (complete response \[CR\] or partial response \[PR\]) according to the International Working Group (IWG) response criteria in myelodysplasia per Cheson et al. 2006. CR was demonstrated by ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow (persistent dysplasia will be noted) and normal findings for hemoglobin, platelet count, neutrophil count, and absence of blasts in the blood. PR was all CR criteria if abnormal before treatment except bone marrow blasts decreased by ≥50% over pre-treatment but still \>5%. Cellularity and morphology are not relevant. Cohort 1 was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 10% using a binomial exact test. The percentage of participants with CR and PR as assessed by the investigator is presented.

  Up to approximately 78.5 months

• Objective Response Rate (ORR) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)

  ORR was defined as the percentage of the participants with either a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) according to the International Myeloma Working Group (IMWG) 2006 response criteria. CR=negative immunofixation of serum and urine+disappearance of soft tissue plasmacytomas+≤5% plasma cells in the bone marrow (BM); sCR=stringent complete response, CR as above+normal serum free light-chain ratio and absence of clonal cells in BM; VGPR=serum+urine M-protein (M-p) by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-p+urine M-p \<100 mg/24 hr; PR=≥50% reduction of serum M-p+reduction in 24-hour urine M-p by ≥90% or to \<200 mg/24 hours. Cohort 2 was evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 25% using a binomial exact test. The percentage of participants with CR, sCR, PR, VGPR as assessed by the investigator is presented.

  Up to approximately 78.5 months

• Complete Remission Rate (CRR) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

  CRR was defined as the percentage of participants with complete remission according to the revised response criteria for malignant lymphoma per Cheson et al. 2007. Complete remission was demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes. Cohort 3 was evaluated statistically by comparing the complete remission for pembrolizumab to a fixed efficacy target of 10% using a binomial exact test. The percentage of participants with complete remission as assessed by the investigator is presented.

  Up to approximately 78.5 months

• Objective Response Rate (ORR) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)

  ORR was defined as the percentage of participants with response (complete response \[CR\] or partial response \[PR\]) according to the revised response criteria for malignant lymphoma per Cheson et al. 2007. CR was demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes. PR was \>50% decrease in the sum of product diameters (SPD) for ≤6 target masses for lymph nodes and \>50% decrease in SPD for a single nodule in greatest transverse diameter for spleen and liver, and no size increase in the lymph nodes, spleen, or liver. The pooled Cohort 4 sub-cohorts were evaluated statistically by comparing the ORR for pembrolizumab to a fixed efficacy target of 25% using a binomial exact test. The percentage of participants with CR and PR as assessed by the investigator is presented.

  Up to approximately 78.5 months

• Objective Response Rate (ORR) in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)

  ORR was evaluated for each of the Cohort 4 sub-cohorts: 4A (primary mediastinal B-cell lymphoma), 4B (grey zone, splenic marginal zone, and mantle cell lymphomas), 4C (follicular lymphoma), and 4D (diffuse large B-Cell lymphoma). ORR was defined as the percentage of participants with response (complete response \[CR\] or partial response \[PR\]) according to the revised response criteria for malignant lymphoma per Cheson et al. 2007. CR was demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes. PR was \>50% decrease in the sum of product diameters (SPD) for ≤6 target masses for lymph nodes and \>50% decrease in SPD for a single nodule in greatest transverse diameter for spleen and liver, and no size increase in the lymph nodes, spleen, or liver. Per protocol, Cohorts 4A, 4B, 4C, and 4D were not planned to be compared to an efficacy target. The percentage of participants with CR and PR as assessed by the investigator is presented.

  Up to approximately 78.5 months

• Objective Response Rate (ORR) in Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide) Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

  ORR was defined as the percentage of participants with response (complete response \[CR\] or partial response \[PR\]) according to the revised response criteria for malignant lymphoma per Cheson et al. 2007. CR was demonstrated by disappearance of all evidence of disease in the bone marrow, spleen, liver, and lymph nodes. PR was \>50% decrease in the sum of product diameters (SPD) for ≤6 target masses for lymph nodes and \>50% decrease in SPD for a single nodule in greatest transverse diameter for spleen and liver, and no size increase in the lymph nodes, spleen, or liver. Per protocol, pooled Cohort 5 was not planned to be evaluated statistically compared to a fixed efficacy target. The percentage of participants with CR and PR as assessed by the investigator is presented.

  Up to approximately 78.5 months

Secondary Outcomes (42)

• Objective Response Rate (ORR) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

  Up to approximately 78.5 months

• Overall Survival (OS)

  Up to approximately 78.5 months

• Overall Survival (OS) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)

  Up to approximately 78.5 months

• Overall Survival (OS) in Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide) Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

  Up to approximately 78.5 months

• Duration of Response (DOR) in Cohort 1: Myelodysplastic Syndrome (MDS)

  Up to approximately 78.5 months

Study Arms (9)

Cohort 1: Myelodysplastic Syndrome (MDS)

EXPERIMENTAL

Participants received pembrolizumab 10 mg/kg by intravenous (IV) infusion on Day 1 of each 14-day cycle.

Biological: Pembrolizumab

Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)

EXPERIMENTAL

Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 21-day cycle OR 10 mg/kg by intravenous (IV) infusion on Day 1 of each 14-day cycle.

Biological: Pembrolizumab

Cohort 3: Relapsed/Refractory (R/R) Hodgkin lymphoma (HL)

EXPERIMENTAL

Participants received pembrolizumab 10 mg/kg by intravenous (IV) infusion on Day 1 of each 14-day cycle.

Biological: Pembrolizumab

Cohort 4A: R/R Primary Mediastinal B-cell Lymphoma (PMBCL)

EXPERIMENTAL

Participants received pembrolizumab 200 mg by IV infusion on Day 1 of each 21-day cycle OR 10 mg/kg by intravenous (IV) infusion on Day 1 of each 14-day cycle.

Biological: Pembrolizumab

Cohort 4B: Other Non-Hodgkin Lymphoma: Grey Zone, Splenic Marginal Zone, and Mantle Cell Lymphomas

EXPERIMENTAL

Participants received pembrolizumab 10 mg/kg by intravenous (IV) infusion on Day 1 of each 14-day cycle.

Biological: Pembrolizumab

Cohort 4C: R/R Follicular Lymphoma (FL)

EXPERIMENTAL

Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.

Biological: Pembrolizumab

Cohort 4D: R/R Diffuse Large B-Cell Lymphoma (DLBCL)

EXPERIMENTAL

Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle.

Biological: Pembrolizumab

Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 20 mg

EXPERIMENTAL

Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle + lenalidomide 20 mg orally (PO) every day (QD) for 21 consecutive days with 7 days off within 28-day cycles.

Biological: Pembrolizumab; Drug: Lenalidomide 20 mg

Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 25 mg

EXPERIMENTAL

Participants received pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle + lenalidomide 25 mg PO QD for 21 consecutive days with 7 days off within 28-day cycles.

Biological: Pembrolizumab; Drug: Lenalidomide 25 mg

Interventions

Pembrolizumab BIOLOGICAL

IV infusion

Also known as: MK-3475, KEYTRUDA®

Cohort 1: Myelodysplastic Syndrome (MDS); Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM); Cohort 3: Relapsed/Refractory (R/R) Hodgkin lymphoma (HL); Cohort 4A: R/R Primary Mediastinal B-cell Lymphoma (PMBCL); Cohort 4B: Other Non-Hodgkin Lymphoma: Grey Zone, Splenic Marginal Zone, and Mantle Cell Lymphomas; Cohort 4C: R/R Follicular Lymphoma (FL); Cohort 4D: R/R Diffuse Large B-Cell Lymphoma (DLBCL); Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 20 mg; Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 25 mg

Lenalidomide 20 mg DRUG

oral capsule

Also known as: REVLIMID®

Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 20 mg

Lenalidomide 25 mg DRUG

oral capsule

Also known as: REVLIMID®

Cohort 5: R/R DLBCL pembrolizumab+lenalidomide 25 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has confirmed diagnosis of relapse or refractory Multiple Myeloma (enrollment completed), Primary mediastinal Large B cell Lymphoma, non-Hodgkin lymphoma (NHL), Follicular Lymphoma, Diffuse Large B cell lymphoma (enrollment discontinued), Hodgkin lymphoma or Myelodysplastic syndrome (enrollment completed).
• Has measurable disease
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
• Demonstrates adequate organ function
• Prior therapy criteria must be met
• Female participants of childbearing potential and male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
• Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy

You may not qualify if:

• Is currently participating in and receiving study therapy or has participated in a study of an investigational agent or used an investigational device within 4 weeks of the first dose of study therapy
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years, has received a live vaccine within 30 days of planned start of study therapy, has received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1, received a monoclonal antibody within 4 weeks prior to study Day 1 or has not recovered from adverse events due to a previously administered agent
• Has known clinically active central nervous system (CNS) involvement
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has evidence of interstitial lung disease, active non-infectious pneumonitis, a known additional malignancy that is progressing or requires active treatment, an active infection requiring intravenous systemic therapy, an active autoimmune disease that has required systemic therapy, a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) infection
• 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 therapy
• Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), 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)
• Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (9)

• Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, Snyder ES, Ricart AD, Balakumaran A, Rose S, Moskowitz CH. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol. 2016 Nov 1;34(31):3733-3739. doi: 10.1200/JCO.2016.67.3467.

  PMID: 27354476 RESULT

• Ribrag V, Avigan DE, Green DJ, Wise-Draper T, Posada JG, Vij R, Zhu Y, Farooqui MZH, Marinello P, Siegel DS. Phase 1b trial of pembrolizumab monotherapy for relapsed/refractory multiple myeloma: KEYNOTE-013. Br J Haematol. 2019 Aug;186(3):e41-e44. doi: 10.1111/bjh.15888. Epub 2019 Apr 1. No abstract available.

  PMID: 30937889 RESULT

• Kuruvilla J, Armand P, Hamadani M, Kline J, Moskowitz CH, Avigan D, Brody JD, Ribrag V, Herrera AF, Morschhauser F, Kanate A, Zinzani PL, Bitran J, Ghesquieres H, Schuster SJ, Farooqui M, Marinello P, Bartlett NL. Pembrolizumab for patients with non-Hodgkin lymphoma: phase 1b KEYNOTE-013 study. Leuk Lymphoma. 2023 Jan;64(1):130-139. doi: 10.1080/10428194.2022.2136956. Epub 2022 Nov 18.

  PMID: 36398795 DERIVED

• Garcia-Manero G, Ribrag V, Zhang Y, Farooqui M, Marinello P, Smith BD. Pembrolizumab for myelodysplastic syndromes after failure of hypomethylating agents in the phase 1b KEYNOTE-013 study. Leuk Lymphoma. 2022 Jul;63(7):1660-1668. doi: 10.1080/10428194.2022.2034155. Epub 2022 Mar 4.

  PMID: 35244520 DERIVED

• Griffin GK, Weirather JL, Roemer MGM, Lipschitz M, Kelley A, Chen PH, Gusenleitner D, Jeter E, Pak C, Gjini E, Chapuy B, Rosenthal MH, Xu J, Chen BJ, Sohani AR, Lovitch SB, Abramson JS, Ishizuka JJ, Kim AI, Jacobson CA, LaCasce AS, Fletcher CD, Neuberg D, Freeman GJ, Hodi FS, Wright K, Ligon AH, Jacobsen ED, Armand P, Shipp MA, Rodig SJ. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma. Blood. 2021 Mar 11;137(10):1353-1364. doi: 10.1182/blood.2020006464.

  PMID: 32871584 DERIVED

• Armand P, Kuruvilla J, Michot JM, Ribrag V, Zinzani PL, Zhu Y, Marinello P, Nahar A, Moskowitz CH. KEYNOTE-013 4-year follow-up of pembrolizumab in classical Hodgkin lymphoma after brentuximab vedotin failure. Blood Adv. 2020 Jun 23;4(12):2617-2622. doi: 10.1182/bloodadvances.2019001367.

  PMID: 32556281 DERIVED

• 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.

  PMID: 31609651 DERIVED

• van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.

  PMID: 31395089 DERIVED

• Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, Chlosta S, Shipp MA, Armand P. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017 Jul 20;130(3):267-270. doi: 10.1182/blood-2016-12-758383. Epub 2017 May 10.

  PMID: 28490569 DERIVED

Related Links

• Merck Oncology Clinical Trials Information

MeSH Terms

Conditions

Myelodysplastic Syndromes; Multiple Myeloma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular

Interventions

pembrolizumab; Lenalidomide

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Lymphoma; Lymphatic Diseases; Lymphoma, B-Cell

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Enrollment of participants into Cohort 5 of this study was discontinued after the Food and Drug Administration (FDA) implemented a clinical hold after determining the risks of pembrolizumab + lenalidomide outweighed any potential benefit.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2013
• First Posted: October 1, 2013
• Study Start: November 22, 2013
• Primary Completion: June 26, 2020
• Study Completion: June 26, 2020
• Last Updated: August 4, 2021
• Results First Posted: July 12, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share