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)

• ClinicalTrials.gov Identifier: NCT03598608
• Recruitment Status: Recruiting
• First Posted: July 26, 2018
• Last Update Posted: October 14, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 16, 2018
• First Posted Date: July 26, 2018
• Last Update Posted Date: October 14, 2022
• Actual Study Start Date: October 17, 2018
• Estimated Primary Completion Date: October 19, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2022)

• Percentage of Participants Experiencing a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 (up to 21 days) ]
  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.
• Percentage of Participants Experiencing an Adverse Event (AE) [ Time Frame: From time of signing informed consent form (ICF) until the end of follow-up (up to approximately 27 months) ]
  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
• Percentage of Participants with Treatment Discontinuations Due to an AE [ Time Frame: From time of signing informed consent form (ICF) until the end of study treatment (up to approximately 24 months) ]
  Percentage of participants discontinuing study treatment due to an AE

Original Primary Outcome Measures (submitted: July 16, 2018)

• Percentage of Participants Experiencing a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 (up to 21 days) ]
  Percentage of participants experiencing a DLT defined by the National Cancer Institute Common Terminology for Adverse Events version 4.0 as:

  • grade (gr) 4 non-hematologic toxicity (not laboratory)
  • gr 4 hematologic toxicity lasting >7 days except platelet count decreased
  • gr 4 platelet count decreased of any duration
  • gr 3 platelet count decreased associated with bleeding
  • any gr 3 non-hematologic toxicity (not laboratory) with the exception of gr 3 nausea, vomiting, or diarrhea (not be considered a DLT unless lasting >3 days despite optimal supportive care)
  • any gr 3 or 4 non-hematologic laboratory abnormality if medical intervention is required, or the abnormality leads to hospitalization, or the abnormality persists for >1 week
  • gr 3 or 4 febrile neutropenia
  • any treatment-related AE which caused participant to discontinue study intervention during the first cycle
  • gr 5 toxicity
  • any treatment-related toxicity which causes a >2-week delay in initiation of Cycle 2
• Percentage of Participants Experiencing an Adverse Event (AE) [ Time Frame: From time of signing informed consent form (ICF) until the end of follow-up (up to approximately 25 months) ]
  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
• Percentage of Participants with Treatment Discontinuations Due to an AE [ Time Frame: From time of signing informed consent form (ICF) until the end of study treatment (up to approximately 24 months) ]
  Percentage of participants discontinuing study treatment due to an AE

Current Secondary Outcome Measures (submitted: February 17, 2022)

• Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 months ]
  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.
• Serum Concentration of Favezelimab [ Time Frame: At designated time points (Up to approximately 25 months) ]
  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.
• Serum Concentration of Pembrolizumab [ Time Frame: At designated time points (Up to approximately 25 months) ]
  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.

Original Secondary Outcome Measures (submitted: July 16, 2018)

• Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 months ]
  ORR is defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all evidence of disease) or a Partial Response (PR: ≥50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses; no increase should be observed in the size of other nodes, liver, or spleen; and splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the greatest transverse diameter) per lymphoma disease response criteria (Cheson et. al., 2007) as assessed by the investigator.
• Serum Concentration of MK-4280 [ Time Frame: At designated time points (Up to approximately 25 months) ]
  Blood samples are to be collected at designated time points for the determination of the serum concentration of MK-4280. 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 drawn at the 30-day follow-up visit.
• Serum Concentration of Pembrolizumab [ Time Frame: At designated time points (Up to approximately 25 months) ]
  Blood samples are to 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 drawn at the 30-day follow-up visit.

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

Descriptive Information

• Brief Title: 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)
• Official Title: 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

Participants in Part B: Randomized cHL-Monotherapy arm in the study will be randomized (1:1 ratio) to receive pembrolizumab or favezelimab.

Primary Purpose: Treatment

Condition

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

Intervention

• Biological: pembrolizumab
  Administered as an IV infusion every 3 weeks (Q3W)
  Other Names:

  • KEYTRUDA®
  • MK-3475
• Biological: Favezelimab
  Administered as an IV infusion Q3W
  Other Name: MK-4280

Study Arms

• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab
• 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).
  Interventions:

  • Biological: pembrolizumab
  • Biological: Favezelimab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 4, 2022): 174
• Original Estimated Enrollment (submitted: July 16, 2018): 134
• Estimated Study Completion Date: October 19, 2027
• Estimated Primary Completion Date: October 19, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Australia, Canada, Germany, Israel, Italy, United States

Administrative Information

• NCT Number: NCT03598608
• Other Study ID Numbers: 4280-003; MK-4280-003 ( Other Identifier: Merck ); 2018-001461-16 ( 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: October 2022