Epcoritamab in Combination With Loncastuximab Tesirine in Relapsed/Refractory Large B-cell Lymphoma (EPCOR+LONCA)

Phase 2 Study of Epcoritamab in Combination With Loncastuximab Tesirine in Relapsed/Refractory Large B-cell Lymphoma

The purpose of this study is to determine whether combining Loncastuximab Tesirine with Epcoritamab is tolerable and effective for reducing and/or eliminating lymphoma cells in the body.

Study Overview

• Status: Recruiting
• Conditions: Relapse; Large B-cell Lymphoma
• Intervention / Treatment: Drug: Epcoritamab; Drug: Loncastuximab Tesirine

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Juan Alderuccio, MD; Phone Number: 305-243-4372; Email: jalderuccio@med.miami.edu

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Contact: Juan Alderuccio, MD; Phone Number: 305-243-4372; Email: jalderuccio@med.miami.edu
      • Principal Investigator: Juan Alderuccio, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men and women aged 18 years or older at the time of signing informed consent.
2. Able and willing to sign the informed consent form (ICF).
3. Ability to comply with the trial protocol.

4. Relapsed/refractory (r/r) large B-cell lymphoma (LBCL) as determined by the local hematopathology laboratory from the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms (Swerdlow et al., 2016):

   1. LBCL or DLBCL, not otherwise specified (NOS)
   2. High-grade B-cell lymphoma (NOS or double/triple hit [technically classified in WHO 2016 as high-grade B-cell lymphoma (HGBCL), with Myc and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) translocations])
   3. Transformed from follicular lymphoma, marginal zone lymphoma (MZL), and nodular lymphocyte predominant Hodgkin lymphoma
   4. Follicular lymphoma stage 3B
   5. Primary mediastinal B-cell lymphoma previously treated with checkpoint inhibitor Note: Relapsed disease is defined as disease that has recurred ≥6 months after completion of therapy. Refractory disease is defined as disease that either progressed during therapy or progressed within 6 months (<6 months) of completion of therapy.
5. Participants who have received at least one prior systemic therapy for LBCL including anti-cluster of differentiation 20 (anti-CD20) monoclonal antibody and anthracycline-containing therapy.
6. Measurable disease by 2014 Lugano Classification. (Participants who have measurable disease, defined as at least 1 bi-dimensionally measurable nodal lesion, defined as >1.5 cm in its longest dimension, or at least 1 bi-dimensionally measurable extra nodal lesion, defined as >1.0 cm in its longest dimension.)
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.

8. Adequate hematologic, hepatic, and renal function tested within 6 weeks prior to the start of therapy (values must not be achieved with growth factors within 72 hs):

   1. Absolute neutrophil count (ANC) ≥ 1.0 × 10^9 cells/L
   2. Hemoglobin ≥8.0 g/dL without blood transfusion in the past week
   3. Platelet count ≥75 × 10^9 platelets/L or ≥ 50 × 10^9 platelets/L if bone marrow involvement or splenomegaly
   4. Total bilirubin ≤1.5 × upper limit normal (ULN). Participants with documented history of Gilbert's syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible (≤3x institutional ULN if lymphoma involvement of the liver).

   5. Alanine transaminase (ALT)/aspartate aminotransferase (AST) ≤3.0 × ULN or ≤5 × ULN in the presence of liver involvement by lymphoma.

      • i. Creatinine within normal institutional limits, or calculated creatinine clearance ≥40 mL/min by the Cockcroft-Gault Equation or other institutional standard methods
9. Willingness to avoid pregnancy during the trial and for at least 12 months after the last dose of the trial intervention.
10. Patients with history of human immunodeficiency virus (HIV) are eligible, provided they are stable on anti-retroviral therapy, have cluster of differentiation 4 (CD4) count ≥200/µL, and have an undetectable viral load. Note: HIV test is optional.
11. Life expectancy of at least 12 weeks
12. For patients receiving glucocorticoid treatment at screening: treatment must be tapered down and administered with a maximum of 25 mg daily in the last 14 days before the first dose of epcoritamab.

Exclusion Criteria:

1. Primary central nervous system (CNS) lymphoma or known CNS involvement by lymphoma at screening as confirmed by magnetic resonance imaging (MRI)/computed tomography (CT) scan (brain) and, if clinically indicated, by lumbar puncture.
2. Prior treatment with anti-cluster of differentiation 19 (anti-CD19) chimeric antigen receptor T-cell (CAR-T) therapy
3. Prior exposure to bispecific T-cell engaging antiCD20XCD3 antibodies
4. Prior autologous or allogenic stem cell transplant

5. Known clinically significant pulmonary disease, including:

   1. Pulmonary fibrosis affecting patient's exercise tolerance.
   2. Chronic obstructive pulmonary disease (COPD) affecting patient's exercise tolerance.

6. Known clinically significant cardiac disease, including:

   1. Onset of unstable angina pectoris within 6 months of signing ICF
   2. Acute myocardial infarction within 6 months of signing ICF
   3. Congestive heart failure (grade III or IV as classified by the New York Heart Association
7. Pregnant or breast feeding
8. Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy.
9. Chronic or current active infectious disease (including severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) requiring systemic antibiotics, antifungal, or antiviral treatment or any major episode of infection requiring treatment with intravenous (IV) antibiotics within 2 weeks of Day 1 of Cycle 1.

10. Exposure to a live vaccine within 30 days of administration or anticipation that a live attenuated vaccine will be required during the study.

    1. Inactivated influenza vaccinations may be given during the influenza season.
    2. An approved coronavirus disease 2019 (COVID-19) vaccine (messenger ribonucleic acid (mRNA), inactivated virus, and replication deficient viral vector vaccines) is allowed.

11. Active hepatitis B infection

    a. Patients who are hepatitis B surface antigen (HbsAg) negative and hepatitis B core antibody (HbcAb) positive must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation

12. Active hepatitis C infection

    a. Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by PCR to be eligible for study participation

13. Patient has no known active SARS-CoV-2 infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the patient must have a negative molecular (eg, PCR) test or 2 negative antigen test results at least 24 hours apart.

    Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations. Patients who do not meet SARS-CoV-2 infection eligibility criteria must be screen-failed and may only rescreen if the following have been met:

    • At least 10 days since first positive test result have passed in asymptomatic patients or at least 10 days since recovery, defined as resolution of fever without use of antipyretics and improvement in symptoms.
14. Patients with severe chronic pulmonary disease, or other serious medical condition which is likely to significantly impair the patient's ability to tolerate the study treatment.
15. Patients with seizure disorder requiring therapy with a last convulsion within two years from enrollment.
16. Patients with impaired decision-making capacity.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: EPCOR in combination with LONCA Treatment Group; Participants in the Epcoritamab (EPCOR) in combination with Loncastuximab (LONCA) treatment group will receive up to 4 cycles of combination EPCOR and LONCA therapy, and an additional 8 cycles of EPCOR therapy, for a total of twelve treatment cycles. Cycles 1 through 3 last 21 days each; cycles four through 12 last 28 days each. Protocol therapy will last approximately 12 months. Total participation duration is approximately 3 years.

Drug: Epcoritamab; Epcoritamab will be administered via subcutaneous injection at the following dose levels and schedule over a total of twelve cycles: Cycle 1 Day 1: Step-up dose of 0.16 mg; Cycle 1 Day 8: Step-up dose of 0.80 mg; Cycle 1 Day 15: First full dose of 48 mg.; Cycles 2 through 4 Days 1, 8 and 15: 48 mg; Cycles 5 through 12 Days 1 and 15: 48 mg; Other Names: Epkinly; Drug: Loncastuximab Tesirine; Loncastuximab will be administered intravenously (IV) at the following dose level and schedule over a total of four cycles: Cycles 1 and 2 Day 1: 120 mcg/kg; Cycles 3 and 4 Day 1: 75 mcg/kg; Cycle 4 Day 22: 75 mcg/kg; Other Names: Zynlonta; Loncatuximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Cytokine Release Syndrome (CRS)-related Toxicity after Epcoritamab Administration	The number of participants experiencing Cytokine Release Syndrome (CRS) toxicity associated with Epcoritamab therapy will be reported, including Grades 2, 3 and 4. CRS-related toxicity will be assessed according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria.	Up to 14 months
Number of Participants Experiencing Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)-related Toxicity	The number of participants experiencing Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)-related toxicity including Grades 2, 3 and 4. ICANS-related toxicity will be assessed according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria.	Up to 14 months
Number of Participants Experiencing Neurologic Toxicities Associated with Epcoritamab	The number of participants experiencing neurologic toxicities associated with Epcoritamab therapy will be reported, including Grades 2, 3 and 4. Neurologic toxicities will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion.	Up to 14 months
Number of Participants Experiencing Fluid Accumulation Associated with Loncastuximab	The number of participants experiencing fluid accumulation associated with Loncastuximab therapy will be reported, including Grades 2, 3 and 4. Fluid accumulation toxicities will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion.	Up to 31 weeks
Number of Participants Experiencing Hepatotoxicity Associated with Loncastuximab	The number of participants experiencing hepatotoxicity (liver-related toxicity) associated with Loncastuximab therapy including Grades 2, 3 and 4 toxicity. Hepatotoxicity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion.	Up to 31 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Overall response rate is defined as the number of participants with complete metabolic response (CMR) or partial metabolic response (PMR) as the best response. Response will be assessed according to Lugano 2014 criteria.	Up to 36 months
Partial Metabolic Response (PMR) Rate	PMR rate is defined as the number of participants with partial metabolic response (PMR) as the best response according to Lugano 2014 criteria.	Up to 36 months
Progression-Free Survival (PFS)	PFS is defined as the elapsed time in months from the start of treatment until disease progression or death, whichever is earlier. Participants who remain alive without progression will be censored at the last documented disease assessment date. Response will assessed according to Lugano 2014 criteria.	Up to 36 months
Overall Survival (OS)	OS is defined as the elapsed time in months from the start of treatment until death from any cause. Alive participants will be censored at the last date known to be alive.	Up to 36 months

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: Genmab; ADC Therapeutics S.A.
• Investigators: Principal Investigator: Juan Alderuccio, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2026
• Primary Completion (Estimated): January 7, 2031
• Study Completion (Estimated): January 7, 2031

Study Registration Dates

• First Submitted: April 2, 2025
• First Submitted That Met QC Criteria: April 2, 2025
• First Posted (Actual): April 9, 2025

Study Record Updates

• Last Update Posted (Actual): March 2, 2026
• Last Update Submitted That Met QC Criteria: February 26, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Recurrence; Antineoplastic Agents, Immunological; Antineoplastic Agents; loncastuximab tesirine
• Other Study ID Numbers: 20241140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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