First-in-Human (FIH) Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

Study Overview
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Brief Summary
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The trial is a global, multi-center safety and efficacy trial of epcoritamab, an antibody also known as EPKINLY™ and GEN3013 (DuoBody®-CD3xCD20). The trial consists of 3 parts: a dose-escalation part (Phase 1, first-in-human (FIH)) an expansion part (Phase 2a) a dose-optimization part (Phase 2a)

Detailed Description
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The purpose of the dose-escalation part of the trial is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D), as well as to establish the safety profile of epcoritamab in patients with relapsed, progressive or refractory B-cell lymphoma. In the expansion part, additional patients will be treated with epcoritamab, at the RP2D and the purpose is to further explore and determine the safety and efficacy of epcoritamab. The dose-optimization part will evaluate alternative priming and intermediate dose regimens of epcoritamab. All patients will receive epcoritamab at the RP2D.

Official Title
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A Phase 1/2, Open-label Safety Trial of GEN3013 in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma (DLBCL), High-grade B-cell Lymphoma (HGBCL), Primary Mediastinal Large B-cell Lymphoma (PMBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Small Lymphocytic Lymphoma (SLL), Marginal Zone Lymphoma (MZL)

Intervention / Treatment
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* Biological: Epcoritamab


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria - Escalation Part (recruitment completed) Documented CD20+ mature B-cell neoplasm DLBCL - de novo or transformed HGBCL PMBCL FL MCL SLL MZL (nodal, extranodal or mucosa associated) Relapsed, progressive and/or refractory disease following treatment with an anti-CD20 monoclonal antibody (e.g. rituximab) potentially in combination with chemotherapy and/or relapsed after autologous stem cell rescue. ECOG performance status 0,1 or 2 Patients must have measurable disease by CT, MRI or PET-CT scan Acceptable renal function Acceptable liver function Main Inclusion Criteria - Expansion & Optimization Parts Documented CD20 positive mature B cell neoplasm or CD20+ MCL DLBCL, de novo or transformed (including double hit or triple hit) PMBCL FL grade 3B Histologic confirmed FL MZL SLL MCL (prior BTKi or intolerant to BTKi) At least 2 therapies including an anti-CD20 monoclonal antibody containing chemotherapy combination regimen Either failed prior autologous hematopoietic stem cell transplantation or ineligible for autologous stem cell transplantation due to age or comorbidities At least 1 measurable site of disease based on CT, MRI or PET-CT scan with involvement of 2 or more clearly demarcated lesions and or nodes Main Exclusion Criteria - All Parts Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening Known past or current malignancy other than inclusion diagnosis AST, and/or ALT >3 × upper limit of normal Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin Estimated CrCl <45 mL/min Known clinically significant cardiovascular disease Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment). Past COVID-19 infection may be a risk factor Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy Seizure disorder requiring therapy (such as steroids or anti-epileptics) Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20 Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior to first epcoritamab administration Eligible for curative intensive salvage therapy followed by high dose chemotherapy with HSCT rescue Autologous HSCT within 100 days prior to first epcoritamab administration, or any prior allogeneic HSCT or solid organ transplantation Active hepatitis B (DNA PCR-positive) or hepatitis C (RNA PCR-positive infection). Subjects with evidence of prior HBV but who are PCR-negative are permitted in Known human immunodeficiency virus (HIV) infection Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF Pregnancy or breast feeding Patient is known or suspected of not being able to comply with the study protocol or has any condition for which, participation would not be in the best interest of the patient Contraindication to all uric acid lowering agents NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epcoritamab<br>Epcoritamab will be administered by subcutaneous injections in cycles of 28 days | Biological: Epcoritamab<br>* Administered as specified in the treatment arm.<br>* Other names: EPKINLY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Escalation part: Incidence of Dose Limiting Toxicities (DLTs) | To determine the RP2D and the MTD, if reached. | During the first cycle (28 days) in each cohort. | 
| Escalation part: Incidence and severity of Adverse Events (AEs) | Treatment-emergent AEs (TEAEs) as assessed by CTCAE v5.0. Abnormal laboratory values are reported as AEs per protocol. | From first dose until the end of the safety follow-up period (4 weeks after last dose) | 
| Expansion part: Objective Response Rate (ORR) | Defined as proportion of participants who have a partial or complete response (PR or CR) following treatment with epcoritamab. Determined by the Lugano response criteria, assessed by the Independent Review Committee (IRC). | From first dose until up to 1 year after the last participant's first dose | 
| Optimization part: Number of participants with cytokine release syndrome (CRS) events |  | From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) | 
| Optimization part: Percentage of participants with =>Grade 2 CRS events |  | From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Escalation & Optimization parts: ORR | Defined as proportion of participants who have a PR or CR following treatment with epcoritamab. Determined by the Lugano response criteria. | From first dose until up to 1 year after the last participant's first dose | 
| Escalation phase: PR rate | Determined by the Lugano response criteria. | From first dose until up to 1 year after the last participant's first dose | 
| All parts: CR rate | Defined as proportion of participants with CR. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in expansion part is reviewed by the IRC. | From first dose until up to 1 year after the last participant's first dose | 
| Expansion part: Time to Response (TTR) | Defined as time to first documentation of objective tumor response (PR or better). Determined by the Lugano and LYRIC response criteria, assessed by the IRC. | From first dose until up to 1 year after the last participant's first dose | 
| All parts: Duration of Response (DOR) | Defined as time from first documentation of response (CR or PR) to the date of progression of disease (PD) or death, whichever occurs earlier. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in the expansion part is reviewed by the IRC. | From first dose until up to 1 year after the last participant's first dose | 
| Expansion & Optimization parts: Duration of CR (DoCR) | Defined as time from first documentation of CR to the date of PD or death, whichever occurs earlier. Determined by the Lugano and LYRIC response criteria, assessed by the IRC. | From first dose until up to 1 year after the last participant's first dose | 
| All parts: Time to next anti-lymphoma therapy (TTNT) | Calculated as time to date of initiation of new anti-lymphoma therapy. | From first dose until up to 1 year after the last participant's first dose | 
| All parts: Progression Free Survival (PFS) | Defined as time to first documented PD or death due to any cause. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (expansion part). Response/disease progression in the expansion part is reviewed by the IRC. | From first dose until up to 1 year after the last participant's first dose | 
| All parts: Overall survival (OS) | Defined as time to death. | From first dose until up to 1 year after the last participant's first dose | 
| Optimization part: Incidence of DLTs |  | From first dose until 7 days after second full dose (Day 28 for DLBCL/MCL; Day 35 for FL) | 
| Optimization part: Number of participants with CRS events |  | From Day 15 (DLBCL/MCL) or Day 22 (FL) until up to 1 year after the last participant's first dose | 
| Optimization part: Percentage of participants with =>Grade 2 CRS events |  | From Day 15 (DLBCL/MCL) or Day 22 (FL) until up to 1 year after the last participant's first dose | 
| Optimization part: Number of participants with CRS events |  | From first dose until up to 1 year after the last participant's first dose | 
| Optimization part: Percentage of participants with =>Grade 2 CRS events |  | From first dose until up to 1 year after the last participant's first dose | 
| Expansion & Optimization parts: Incidence and severity of AEs | TEAEs as assessed by CTCAE v5.0. Abnormal laboratory values are reported as AEs per protocol. | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| All parts: Area-under-the-concentration-time curve from Time 0 to Time of last dose (AUClast) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: AUC from Time 0 to Infinity (AUCinf) |  | From first dose until treatment discontinuation, expected average of 1 year. | 
| All parts: Maximum (peak) plasma concentration (Cmax) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Time to reach Cmax (Tmax) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Pre-dose (trough) concentrations (Cthrough) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Elimination half-life (t 1/2) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Total body clearance of drug from the plasma (CL) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Volume of distribution (Vd) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| All parts: Incidence of anti-drug antibodies (ADA) |  | From first dose until up to 1 year after the last participant's first dose | 
| Expansion & Optimization parts: Percentage of participants with Minimal Residual Disease (MRD) negativity status | Defined as proportion of participants with at least one MRD negative result. | From first dose until up to 1 year after the last participant's first dose | 
| Expansion & Optimization parts: Duration of MRD negative status | Defined as the number of days from the first documentation of MRD negative status to the date of MRD status change (not MRD negative). | From first dose until up to 1 year after the last participant's first dose | 
| Expansion part: Changes in lymphoma symptoms as measured by the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) | Monitor change from baseline in health-related quality of life over time and in relation to treatment. | From first dose until up to 1 year after the last participant's first dose |