Trial of the Safety and Efficacy of Epcoritamab in Japanese Subjects With R/R B-NHL

Study Overview
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Brief Summary
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The trial is an open-label, multi-center safety and preliminary efficacy trial of epcoritamab (EPKINLY™) in Japanese patients with relapsed, progressive or refractory B-cell lymphomas and Japanese patients with B-cell lymphomas that have achieved partial response (PR) or complete response (CR) following prior SOC. The trial consists of two parts: Part 1, dose escalation (phase 1), and Part 2, expansion (phase 2). 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 Japanese patients with relapsed, progressive or refractory B-cell lymphoma and Japanese patients with B-cell lymphomas that have achieved partial response (PR) or complete response (CR). 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. Part 2 of the trial will be initiated once the RP2D has been determined in Part 1. In Part 2, epcoritamab is investigated as a monotherapy and in combination with other standard of care (SOC) agents.

Detailed Description
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All participants in the trial will receive epcoritamab, as monotherapy or in combination with SOC. The following regimens will be investigated in Part 2: Arm 1: epcoritamab monotherapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) Arm 2: epcoritamab + rituximab and lenalidomide (R2) in patients with R/R FL Arm 3: epcoritamab + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated DLBCL with high risk features Arm 4: epcoritamab + gemcitabine and oxaliplatin (GemOx) in patients with R/R DLBCL who either failed prior autologous hematopoietic stem cell transplantation (ASCT), or are ineligible for autologous HSCT. Arm 5: epcoritamab maintenance in patients with FL who achieve a complete response (CR) or a partial response (PR) following 1L/2L SOC treatment

Official Title
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Safety and Preliminary Efficacy of Epcoritamab (GEN3013; DuoBody®-CD3×CD20) in Japanese Subjects With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma - A Phase 1/2, Open-Label, Dose-Escalation Trial With Expansion Cohorts

Conditions
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Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Follicular Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: epcoritamab (monotherapy)
* Biological: epcoritamab
* Drug: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
* Drug: gemcitabine and oxaliplatin
* Biological: epcoritamab (maintenance)
* Drug: rituximab and lenalidomide


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: • Must be at least 20 years of age, inclusive • Japanese subjects • CD20 positivity at representative tumor biopsy Part 1: Diffuse large B-cell lymphoma (de novo or histologically transformed) High-grade B-cell lymphoma Primary mediastinal large B-cell lymphoma Follicular lymphoma Marginal zone lymphoma (nodal, extranodal of mucosa-associated lymphoid tissue, or splenic) Small lymphocytic lymphoma Part 2 : Arm 1: Diffuse large B-cell lymphoma (de novo or histologically transformed) Follicular lymphoma grade 1-3A Relapsed or refractory disease and previously treated with at least 2 lines of systemic antineoplastic therapy including at least 1 anti-CD20 mAb-containing therapy. Measurable disease by CT, MRI or PET-CT scan Arm 2: • R/R FL grade 1, 2 or 3a, stage II, III, or IV, without evidence of transformation. Previously treated with at least 1 prior anti-neoplastic agent, including anti-CD20 antibody Must have a need for treatment initiation based on symptoms and/or disease burden (GELF criteria) Eligible to receive R2 per investigator determination Arm 3: One of following confirmed histologies (de novo or histologically transformed from FL or nodal marginal zone lymphoma) : o DLBCL, NOS o Double-hit or triple-hit DLBCL FL Grade 3B. T-cell/histiocyte rich LBCL International Prognostic Index (IPI) score ≥3 No prior therapy for DLBCL or FL G3B other than nodal biopsy, corticosteroids, or palliative radiotherapy. Eligible to receive R-CHOP per investigator determination Arm 4: One of following confirmed histologies (de novo or histologically transformed from FL or nodal marginal zone lymphoma) including: o DLBCL, NOS. o Double-hit or triple-hit DLBCL o FL Grade 3B. o T-cell/histiocyte rich LBCL Relapsed or refractory to at least one prior therapy including at least one prior anti-CD20 antibody. Either failed prior autologous hematopoietic stem cell transplantation (ASCT), or ineligible for autologous HSCT Eligible to receive GemOx per investigator determination Arm 5: • History of histologically confirmed CD20+ FL Grade 1-3a without evidence of transformation. • In CR or PR per Lugano criteria following first-line or second-line treatment with SOC regimen, including anti-CD20 antibody, and last dose of SOC within 6 months prior to enrollment Main Exclusion Criteria: • Primary CNS lymphoma or CNS involvement by lymphoma at screening • Subjects not eligible for high dose therapy with autologous hematopoietic stem cell transplantation due to personal choice, social issues, or similar • Known clinically significant cardiac disease Chronic ongoing infectious diseases requiring treatment (excluding prophylactic treatment) Exclusion criteria for Part 2, Arms 2 through 5: Arm 2: • FL Grade 3b • Histologic evidence of transformation to an aggressive lymphoma Contraindication to rituximab or lenalidomide Unwilling or unable to take aspirin prophylaxis or prophylactic anticoagulant as clinically indicated Arm 3: • Contraindication to any of the individual drugs of the R-CHOP regimen Arm 4: • Contraindication to any of the individual drugs of the GemOx regimen Arm 5: FL Grade 3b Histologic evidence of transformation to an aggressive lymphoma

Ages Eligible for Study
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Minimum Age: 20 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: Sequential Assignment
Interventional Model Description: Part 1: Sequential Assignment Part 2: Parallel Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: arm 1: epcoritamab<br>In subjects with DLBCL/FL | Biological: epcoritamab (monotherapy)<br>* Epcoritamab will be administered subcutaneously in cycles of 4 weeks (i.e. 28 days)<br>* Other names: EPKINLY™;|
| Experimental: arm 2: epcoritamab + rituximab + lenalidomide<br>In subjects with relapsed/refractory FL | Biological: epcoritamab<br>* Epcoritamab will be administered in combination with the respective SOC chemotherapy followed by epcoritamab monotherapy.<br>* Other names: EPKINLY™;Drug: rituximab and lenalidomide<br>* 28-day cycles.<br>* Other names: R2;|
| Experimental: arm 3: epcoritamab + rituximab + cyclophosphamide+ doxorubicin+ vincristine + prednisone<br>In subjects with previously untreated DLBCL | Biological: epcoritamab<br>* Epcoritamab will be administered in combination with the respective SOC chemotherapy followed by epcoritamab monotherapy.<br>* Other names: EPKINLY™;Drug: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone<br>* 21-day cycles<br>* Other names: R-CHOP;|
| Experimental: arm 4: epcoritamab + gemcitabine + oxaliplatin<br>In subjects with relapsed/refractory DLBCL | Biological: epcoritamab<br>* Epcoritamab will be administered in combination with the respective SOC chemotherapy followed by epcoritamab monotherapy.<br>* Other names: EPKINLY™;Drug: gemcitabine and oxaliplatin<br>* 28-day cycles<br>* Other names: Gemox;|
| Experimental: arm 5: epcoritamab maintenance<br>In subjects with FL in complete response (CR) or in partial response (PR) following first line or second line SOC treatment | Biological: epcoritamab (maintenance)<br>* 28-day cycle for Cycle 1 and then 56-day cycle from Cycle 2 through 13<br>* Other names: EPKINLY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Incidence and severity of Adverse Events (AEs) | Treatment emergent AEs. | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Part 1: Incidence of Dose limiting toxicities (DLTs) | To determine the RP2D and the MTD, if reached. | DLTs are assessed during the first cycle (28 days) in each cohort | 
| Part 2, Arm 1: Objective response rate (ORR) | Antitumor activity as measured by the ORR according to Lugano classification | From 6 weeks after enrollment until treatment discontinuation, assessed up to 3 years | 
| Part 2, Arms 2-4: Incidence of DLTs |  | DLTs are assessed during the first cycle (28 days) in arms 2-4 | 
| Part 2, Arms 2-5: Incidence and severity of AEs | Treatment emergent AEs (TEAEs) | From first dose until the end of the safety follow-up period (60 days after last dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Both 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 | 
| Both parts: AUC from Time 0 to Infinity (AUCinf) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Maximum (peak) plasma concentration (Cmax) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Time to reach Cmax (Tmax) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Pre-dose (trough) concentrations (Cthrough) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Total body clearance of drug from the plasma (CL) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Volume of distribution (Vd) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Elimination half-life (t 1/2) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Both parts: Incidence of Anti-Drug-Antibodies (ADAs) |  | From first dose until treatment discontinuation, expected average of 1 year | 
| Part 1 and Part 2, Arm1: Number of participants with clinically significant shifts from baseline in clinical laboratory parameters | Clinical laboratory parameters assessed: biochemistry, hematology | From first dose until treatment discontinuation, expected average of 1 year | 
| Part 2, Arm1: Incidence and severity of AEs | TEAEs as assessed by CTCAE V5.0. | From first dose until the end of the safety follow-up period (60 days after last dose) | 
| Part 1 and Part 2, arms 2-5: ORR | Defined as proportion of participants who have a PR or CR following treatment with epcoritamab. Determined by the Lugano response criteria. | Approximately 3 years after the last subject's first dose | 
| Both parts: CR rate | Defined as proportion of participants with CR. Determined by the Lugano response criteria (both parts) and by the LYRIC response criteria (Part 2, arm 1). Response/disease progression in Part 2, arm 1 is reviewed by the IRC. | Approximately 3 years after the last subject's first dose | 
| Both 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 (Part 2, arm 1). Response/disease progression in the expansion part is reviewed by the IRC. | Approximately 3 years after the last subject's first dose | 
| Both 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 (Part 2, arm 1). Response/disease progression in the expansion part is reviewed by the IRC. | Approximately 3 years after the last subject's first dose | 
| Part 2: 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 | Approximately 3 years after the last subject's first dose | 
| Part 2: 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. | Approximately 3 years after the last subject's first dose | 
| Part 1 and Part 2 arm 1: Time to next anti-lymphoma therapy (TTNT) | Calculated as time to date of initiation of new anti-lymphoma therapy. | Approximately 3 years after the last subject's first dose | 
| Both parts: Overall Survival (OS) | Defined as time to death. | Approximately 3 years after the last subject's first dose |