A Study to Evaluate Change in Disease Activity of Subcutaneous (SC) Epcoritamab Combined With Intravenous and Oral Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine, and Prednisone (R-CHOP) or R-CHOP in Adult Participants With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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B-cell Lymphoma is an aggressive and rare cancer of a type of immune cells (a white blood cell responsible for fighting infections). The purpose of this study is to assess the change in disease activity of epcoritamab when combined with intravenous and oral rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or R-CHOP in adult participants globally with diffuse large b-cell lymphoma (DLBCL). Change in disease activity will be assessed. Epcoritamab is an investigational drug being developed for the treatment of DLBCL. Study doctors put the participants in groups called treatment arms. Participants will receive epcoritamab combined with R-CHOP, followed by epcoritamab or R-CHOP followed by rituximab will be explored. Approximately 900 adult participants with with newly diagnosed DLBCL will be enrolled in the study in approximately 315 sites in globally. In the Arm 1, participants will receive subcutaneous epcoritamab combined with intravenous and oral R-CHOP followed by subcutaneous epcoritamab in 21-day cycles. In the Arm 2, participants will receive intravenous and oral R-CHOP followed by intravenous rituximab in 21-day cycles. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.

Official Title
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A Phase 3, Randomized, Open-Label Study to Evaluate Safety and Efficacy of Epcoritamab in Combination With R-CHOP Compared to R-CHOP in Subjects With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Epcoritamab
* Drug: Cyclophosphamide
* Drug: Rituximab
* Drug: Vincristine
* Drug: Doxorubicin
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Planned to receive treatment with 6 cycles of standard rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) per investigator determination. Must have newly diagnosed, histologically confirmed CD20+ diffuse large b-cell lymphoma [DLBCL] (de novo or histologically transformed from a diagnosis of follicular lymphoma) at most recent representative tumor biopsy based on the pathology report, with a World Health Organization (WHO) 2016 classification and including: DLBCL, Not Otherwise Specified (NOS). High grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement with DLBCL morphology. T-cell/histiocyte-rich large B-cell lymphoma. Epstein Barr virus-positive DLBCL, NOS. Follicular lymphoma Grade 3b. Note: The local pathology report must be available at Screening to support CD20+ DLBCL histology. Composite/intermediate histology with any of the following components is not allowed: high grade B-cell lymphoma, NOS; Hodgkin's lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt; plasmablastic lymphoma or any CD20- lymphoma, such as anaplastic lymphoma kinase-positive large B-cell lymphoma, human herpesvirus type 8-positive DLBCL, or primary effusion lymphoma. Availability of archival or freshly collected tumor tissue at Screening. Archival paraffin-embedded tissue must be obtained within 8 weeks prior to Cycle 1 Day 1. Must have an IPI score of 2-5. The number of participants with IPI 2 will not exceed approximately 30% of the overall sample size. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 prior to initiating R-CHOP treatment. Note that participant with an initial ECOG performance status >= 3 may be screened if pre-phase treatment is planned. Participant may be eligible if ECOG performance status were to improve to 0-2 during pre-phase treatment. Has at least one target lesion defined as: >= 1 measurable nodal lesion (long axis > 1.5 cm ) or >= 1 measurable extra-nodal lesion (long axis > 1 cm) on computed tomography (CT) scan or magnetic resonance imaging (MRI). AND Positron emission tomography (PET)-positive on PET-CT scan. Laboratory values meeting the criteria laid out in the protocol. Left ventricular ejection fraction must be >= 50% by multi-gated acquisition or transthoracic echocardiography at Screening. Exclusion Criteria: History of prior systemic anti-lymphoma therapy for diagnosed diffuse large b-cell lymphoma (DLBCL) including any definitive radiotherapy with curative intent] other than corticosteroids with or without vincristine during prephase treatment, or non-curative intent palliative radiotherapy with the stipulation that radiated lesions cannot be selected as target lesion for response assessment. Clinically significant cardiovascular disease as per the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epcoritamab and R-CHOP<br>Participants will receive subcutaneous epcoritamab combined with intravenous and oral rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) followed by epcoritamab in 21-day cycles. | Drug: Epcoritamab<br>* Subcutaneous Injection (SC)<br>* Other names: ABBV-GMAB-3013;Drug: Cyclophosphamide<br>* Intravenous (IV) Injection<br>Drug: Rituximab<br>* IV Infusion<br>Drug: Vincristine<br>* IV Infusion<br>Drug: Doxorubicin<br>* IV Infusion<br>Drug: Prednisone<br>* Oral; Tablet<br>|
| Experimental: R-CHOP and Rituximab<br>Participants will receive intravenous and oral R-CHOP followed by intravenous rituximab in 21-day cycles. | Drug: Cyclophosphamide<br>* Intravenous (IV) Injection<br>Drug: Rituximab<br>* IV Infusion<br>Drug: Vincristine<br>* IV Infusion<br>Drug: Doxorubicin<br>* IV Infusion<br>Drug: Prednisone<br>* Oral; Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Progression-Free Survival (PFS) with an International Prognostic Index (IPI) of 3-5 | PFS is defined as the duration from randomization to the date of disease progression as determined by Lugano 2014 criteria as assessed by Independent Review Committee (IRC), or death due to any cause whichever comes first. | Up to Approximately 46 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with PFS | PFS is defined as the duration from randomization to the date of disease progression as determined by Lugano 2014 criteria as assessed by IRC, or death due to any cause, whichever occurs first. | Up to Approximately 46 Months | 
| Number of Participants with Event-free survival (EFS) | EFS is defined as the duration from randomization to the date of disease progression determined by Lugano criteria as assessed by IRC, IRC-assessed PR or SD followed by non protocol-specified NALT, a positive biopsy on or after end-of-treatment (EOT), regardless of whether NAL initiated, or death from any cause. | Up to Approximately 46 Months | 
| Percentage of Participants with Complete Remission (CR) | CR is defined as the absence of lymphoma determined by fluorodeoxyglucose positron emission tomography (FDG-PET),determined by Lugano 2014 criteria as assessed by IRC. | On or After to Approximately 28 Weeks | 
| Overall survival (OS) | OS is defined as time from randomization until death due to any causes. | Up to Approximately 76 Months | 
| Percentage of Participants with Minimal Residual Disease (MRD) Negativity | The MRD negativity rate is defined as the percentage of participants who achieve MRD negativity prior to the initiation of any non-protocol-specified new anti-lymphoma therapy. | Up to Approximately 46 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Non-Hodgkins Lymphoma, Cancer, Epcoritamab, ABBV-GMAB-3013, R-CHOP, Rituximab, EPCORE