Study to Evaluate the Safety and Efficacy of a Combination of Favezelimab (MK-4280) and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies (MK-4280-003)

A Phase 1/Phase 2 Clinical Study to Evaluate the Safety and Efficacy of a Combination of MK-4280 and Pembrolizumab (MK-3475) in Participants With Hematologic Malignancies

This study will evaluate the safety and efficacy of favezelimab (MK-4280) in combination with pembrolizumab (MK-3475) using a non-randomized study design in participants with the following hematological malignancies:

• classical Hodgkin lymphoma (cHL)
• diffuse large B-cell lymphoma (DLBCL)
• indolent non-Hodgkin lymphoma (iNHL)

This study will also evaluate the safety and efficacy of pembrolizumab or favezelimab administered as monotherapy in participants with cHL using a 1:1 randomized study design.

The study will have 2 phases: a safety lead-in and an efficacy expansion phase. The recommended Phase 2 dose (RP2D) will be determined in the safety lead-in phase by evaluating dose-limiting toxicities.

There is no primary hypothesis for this study.

Study Overview

• Status: Completed
• Conditions: Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Hodgkin Disease
• Intervention / Treatment: Biological: pembrolizumab; Biological: Favezelimab

Detailed Description

Per protocol amendment 7, the secondary serum concentration endpoints were removed and will not be reported.

• Study Type: Interventional
• Enrollment (Actual): 137
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation & General Hospital ( Site 0203)
  • Queensland
    • Woollongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital ( Site 0204)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health ( Site 0201)
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent s Hospital (Melbourne) Limited ( Site 0202)
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1L3
      • BC Cancer ( Site 0107)
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba ( Site 0101)
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre ( Site 0100)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital ( Site 0105)
• Germany
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • U. klinikum Koeln AOER ( Site 0326)
  • Saxony
    • Leipzig, Saxony, Germany, 4103
      • Universitaetsklinikum Leipzig AOeR ( Site 0327)
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center ( Site 0382)
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Jerusalem ( Site 0383)
  • Ramat Gan, Israel, 5262001
    • Chaim Sheba Medical Center. ( Site 0380)
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 0381)
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O. Universitaria Policlinico S. Orsola-Malpighi ( Site 0351)
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy, 47014
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori ( Site 0354)
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Humanitas-U.O di Oncologia medica ed Ematologia ( Site 0352)
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center ( Site 0020)
  • California
    • Duarte, California, United States, 91010
      • City of Hope ( Site 0001)
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center (Radiological Sciences) ( Site 0007)
    • Monterey, California, United States, 93940
      • Pacific Cancer Care ( Site 0006)
    • San Francisco, California, United States, 94143
      • University of California San Francisco ( Site 0023)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute ( Site 0002)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center ( Site 0019)
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology-Austin Midtown ( Site 8002)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has measurable disease, defined as ≥1 lesion that can be accurately measured in 2 dimensions with diagnostic quality cross sectional anatomic imaging (computed tomography or magnetic resonance imaging). Minimum measurement must be >15 mm in the longest diameter or >10 mm in the short axis
• Is able to provide a core or excisional tumor biopsy for biomarker analysis from an archival (within 3 months) or newly obtained biopsy at screening
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)

Exclusion Criteria:

• Has known clinically active central nervous system (CNS) involvement
• Has received prior therapy with an anti-lymphocyte activation gene-3 (LAG-3) antibody
• Has received chimeric antigen receptors (CAR)-T-cell therapy for cHL and DLBCL Cohorts
• Has received prior anticancer therapy or thoracic radiation therapy within 14 days before the first dose of study treatment
• Has ≥Grade 2 non-hematological residual toxicities from prior therapy
• Has had a prior anticancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to agents administered ≥4 weeks earlier
• Has received a live vaccine within 30 days prior to first dose of study treatment. Administration of killed vaccines are allowed
• Has received an investigational agent or used an investigational device within 4 weeks prior to intervention administration
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug
• Has a known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has an active infection requiring intravenous systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has known, active hepatitis B or hepatitis C infection
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Has had an allogeneic hematopoetic stem cell/solid organ transplantation within the last 5 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Favezelimab Dose A+pembrolizumab; Participants receive 200 mg pembrolizumab by intravenous (IV) infusion followed by favezelimab Dose A by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part A: Favezelimab Dose B+pembrolizumab; Participants receive 200 mg pembrolizumab by IV infusion followed by favezelimab Dose B by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part A: Favezelimab Dose C+Pembrolizumab; Participants receive 200 mg pembrolizumab by IV infusion followed by favezelimab Dose C by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part B: cHL-Combination Therapy; Participants with cHL receive 200 mg pembrolizumab by IV infusion followed by the recommended Phase 2 dose (RP2D) of favezelimab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part B: DLBCL-Combination Therapy; Participants with DLBCL receive 200 mg pembrolizumab by IV infusion followed by the RP2D of favezelimab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part B: iNHL-Combination Therapy; Participants with iNHL receive 200 mg pembrolizumab by IV infusion followed by the RP2D of favezelimab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280
Experimental: Part B: Randomized cHL-Monotherapy; Participants with cHL receive either pembrolizumab by IV infusion or the RP2D of favezelimab by IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles (up to approximately 2 years).	Biological: pembrolizumab; Administered as an IV infusion every 3 weeks (Q3W); Other Names: MK-3475; KEYTRUDA®; Biological: Favezelimab; Administered as an IV infusion Q3W; Other Names: MK-4280

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Experiencing a Dose-limiting Toxicity (DLT)	DLT will be defined as any drug-related adverse event (AE) observed during the DLT evaluation period (Cycle 1) that results in a change to a given dose or a delay in initiating the next cycle and reported as the percentage of participants experiencing a DLT defined by the National Cancer Institute Common Terminology for Adverse Events version 4.0.	Cycle 1 (up to 21 days)
Percentage of Participants Experiencing an Adverse Event (AE)	Percentage of participants experiencing an AE defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment	From time of signing informed consent form (ICF) until the end of follow-up (up to approximately 27 months)
Percentage of Participants with Treatment Discontinuations Due to an AE	Percentage of participants discontinuing study treatment due to an AE	From time of signing informed consent form (ICF) until the end of study treatment (up to approximately 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the percentage of participants in the analysis population who had a Complete Response or a Partial Response per lymphoma disease response criteria (Cheson et. al., 2007) as assessed by the investigator.	Up to approximately 24 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Armand P, Zinzani PL, Timmerman J, Johnson NA, Lavie D, Thiagarajan K, Topp BG, Pillai P, Herrera AF. Estimating efficacy of favezelimab plus pembrolizumab relative to pembrolizumab in anti-PD-1-refractory Hodgkin lymphoma. Blood Adv. 2025 Oct 14;9(19):4987-4995. doi: 10.1182/bloodadvances.2024014654.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2018
• Primary Completion (Actual): January 28, 2026
• Study Completion (Actual): January 28, 2026

Study Registration Dates

• First Submitted: July 16, 2018
• First Submitted That Met QC Criteria: July 16, 2018
• First Posted (Actual): July 26, 2018

Study Record Updates

• Last Update Posted (Actual): February 5, 2026
• Last Update Submitted That Met QC Criteria: February 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1); programmed cell death ligand 2 (PD-L2, PDL2)
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Hodgkin Disease; Parkinson Disease 4, Autosomal Dominant Lewy Body; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab
• Other Study ID Numbers: 4280-003; MK-4280-003 (Other Identifier: MSD); 2018-001461-16 (EudraCT Number); 2023-503587-17-00 (Registry Identifier: EU CT); U1111-1287-5405 (Registry Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No