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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hodgkin Disease, Lymphoma, Non-Hodgkin, Lymphoma, B-Cell

Intervention / Treatment
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* Biological: pembrolizumab
* Biological: Favezelimab


Participation Criteria
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Eligibility Criteria
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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

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Favezelimab Dose A+pembrolizumab<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose B+pembrolizumab<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part A: Favezelimab Dose C+Pembrolizumab<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part B: cHL-Combination Therapy<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part B: DLBCL-Combination Therapy<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part B: iNHL-Combination Therapy<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|
| Experimental: Part B: Randomized cHL-Monotherapy<br>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<br>* Administered as an IV infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Favezelimab<br>* Administered as an IV infusion Q3W<br>* Other names: MK-4280;|

What is the study measuring?
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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 | 
| Serum Concentration of Favezelimab | Blood samples will be collected at designated time points for the determination of the serum concentration of favezelimab. For Cycles 1 and 8: Day 1 at predose, end of infusion, and 4 hours postdose; Days 8 and 15 at any time. Cycles 2 through 7, Cycles 9 through 16 and every 4 cycles thereafter: Day 1 at predose. Blood samples will also be collected at the 30-day follow-up visit. | At designated time points (Up to approximately 25 months) | 
| Serum Concentration of Pembrolizumab | Blood samples will be collected at designated time points for the determination of the serum concentration of pembrolizumab. For Cycles 1 and 8: Day 1 at predose, end of infusion, and 4 hours postdose; Days 8 and 15 at any time. Cycles 2 through 7, Cycles 9 through 16 and every 4 cycles thereafter: Day 1 at predose. Blood samples will also be collected at the 30-day follow-up visit. | At designated time points (Up to approximately 25 months) | 

 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)