Clinical trial NCT01953692: A Trial of Pembrolizumab (MK-3475) in Participants With Blood Cancers (MK-3475-013/KEYNOTE-013)
Official title: A Phase Ib Multi-Cohort Trial of MK-3475 (Pembrolizumab) in Subjects With Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-10-01
Enrollment: 197
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Number of Participants Who Experienced One or More Adverse Events (AEs):
timeFrame: Up to approximately 78.5 months
measure: Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Complete Remission Rate (CRR) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: 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)
timeFrame: Up to approximately 78.5 months
Secondary outcomes:
measure: Objective Response Rate (ORR) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 78.5 months
measure: Overall Survival (OS) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: 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)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: Duration of Response (DOR) in Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide) Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Positive Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide): Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Negative Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide): Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
timeFrame: Up to approximately 78.5 months
measure: Objective Response Rate (ORR) in Programmed Cell Death Ligand 1 (PD-L1) Indeterminate Participants Pooled From Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide): Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
timeFrame: Up to approximately 78.5 months
measure: Progression-free Survival (PFS) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Progression-free Survival (PFS) in Cohort 3: Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)
timeFrame: Up to approximately 78.5 months
measure: Progression-free Survival (PFS) in Participants Pooled From the Cohort 4 Non-Hodgkin Lymphoma (NHL) Sub-Cohorts (Cohorts 4A+4B+4C+4D)
timeFrame: Up to approximately 78.5 months
measure: Progression-free Survival (PFS) in the Cohort 4 Non-Hodgkin Lymphoma (NHL) Individual Sub-Cohorts (Cohorts 4A, 4B, 4C, and 4D)
timeFrame: Up to approximately 78.5 months
measure: Progression-free Survival (PFS) in Participants Pooled From the Cohort 5 (Pembrolizumab + 20 or 25 mg Doses of Lenalidomide) Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)
timeFrame: Up to approximately 78.5 months
measure: Marrow Complete Response (mCR) in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Cytogenic Complete Response in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Cytogenic Partial Response in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Erythroid Response in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Neutrophil Response in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Platelet Response in Cohort 1: Myelodysplastic Syndrome (MDS)
timeFrame: Up to approximately 78.5 months
measure: Time to Progression (TTP) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Stringent Complete Remission (sCR) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
measure: Complete Response (CR) in Cohort 2: Relapsed Refractory/Refractory (rR/R) Multiple Myeloma (MM)
timeFrame: Up to approximately 78.5 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.