Epcoritamab + Rituximab + Lenalidomide for Lymphoma

(EPCORE™FL-2 Trial)

Recruiting at 326 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Genmab

Disqualifiers: Major surgery, Active CMV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 120 weeks

1095 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find a better treatment for follicular lymphoma (FL), a type of blood cancer affecting immune cells that is difficult to cure with current treatments. Researchers are investigating whether adding epcoritamab, a new potential drug, to standard medicines like rituximab and lenalidomide, or other chemoimmunotherapy options, can manage the disease more effectively. People with FL who have not yet received treatment and require systemic treatment, such as those with large tumors or specific symptoms, may be suitable for this study. Participants will receive different treatment combinations and must visit the hospital regularly for check-ups. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop your current medications. It's best to discuss this with the study doctors to understand how your current medications might interact with the trial treatments.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that the combination of epcoritamab, rituximab, and lenalidomide achieved key effectiveness goals in treating follicular lymphoma. Safety data suggests this combination is generally well-tolerated, though side effects can occur. Common side effects might include fatigue or reactions at the injection site.

Studies have shown that lenalidomide and rituximab alone are well-tolerated and effective for certain types of lymphoma, with manageable side effects. This treatment is widely used.

The trial also includes chemoimmunotherapy options, standard treatments for lymphoma. These treatments have known side effects, such as possible nausea or low blood counts, but doctors are adept at managing them.

Overall, the treatments in this study have been tested in various settings, and their safety is well-documented. However, individual experiences can vary, so discussing any concerns with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about epcoritamab combined with lenalidomide and rituximab (R2) for lymphoma because this combination offers a novel approach by harnessing the power of immunotherapy. Unlike traditional chemotherapy options like CHOP or R-CHOP, which use drugs to kill cancer cells directly, epcoritamab is a bispecific antibody that helps the immune system target and destroy lymphoma cells more effectively. This mechanism could potentially lead to more precise targeting of cancer cells with fewer side effects. Additionally, combining it with lenalidomide and rituximab may enhance overall effectiveness by leveraging multiple pathways to attack the cancer.

What evidence suggests that this trial's treatments could be effective for follicular lymphoma?

Research shows that a combination of epcoritamab, lenalidomide, and rituximab holds promise for treating follicular lymphoma. In this trial, participants in Arm A1 and Arm A2 will receive this combination, with Arm A1 having a longer treatment duration. Studies involving this combination in patients whose disease has returned or not responded to other treatments have reported better survival rates and slower disease progression. Specifically, these studies found a significant improvement in patient response to treatment and in the duration of disease-free survival.

Meanwhile, participants in Arm C will receive lenalidomide and rituximab. Research has shown a high response rate for this pair, with some studies reporting that 92% of patients responded to treatment, and 64% achieved a complete response. This suggests that both treatment options in this trial have strong potential for effectively managing follicular lymphoma. ^{1 5 6 7 8}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

Adults with previously untreated Follicular Lymphoma (FL) who need systemic treatment and meet specific medical criteria, including a certain stage of disease and tumor size. They must be able to follow the study procedures and have an acceptable performance status for daily activities.

Inclusion Criteria

I need treatment for my condition as per my doctor's assessment.

My PET/CT scan shows active cancer spots.

I am eligible for standard cancer treatments like CIT or R2.

Exclusion Criteria

I am currently suffering from an active CMV infection.

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive R2 (rituximab and lenalidomide) alone or in combination with epcoritamab, or investigator's choice chemoimmunotherapy for 120 weeks

120 weeks

Regular visits at a hospital or clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

What Are the Treatments Tested in This Trial?

Interventions

• Epcoritamab

Trial Overview The trial is testing the safety and effectiveness of Epcoritamab combined with Rituximab and Lenalidomide in treating FL. Participants are divided into groups receiving different treatments, including standard chemoimmunotherapy options, over a period of 120 weeks.

How Is the Trial Designed?

Group I: Arm C: Lenalidomide and Rituximab (R2) Experimental Treatment 2 Interventions

Participants will receive lenalidomide and rituximab (R2) during the 120 week treatment duration.

Group II: Arm B: Chemoimmunotherapy (CIT) Option B Experimental Treatment 4 Interventions

Participants will receive CIT Option B (G and bendamustine (Benda) \[G-Benda\]/R-Benda during the 120 week treatment duration.

Group III: Arm B: Chemoimmunotherapy (CIT) Option A Experimental Treatment 6 Interventions

Participants will receive CIT Option A (obinutuzumab (G) and cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) \[G-CHOP\]/ rituximab (R)-CHOP during the 120 week treatment duration.

Group IV: Arm A2: Epcoritamab + Lenalidomide and Rituximab (R2) Experimental Treatment 3 Interventions

Participants will receive epcoritamab in combination with R2 (ER2), during the 24 week treatment duration.

Group V: Arm A1: Epcoritamab + Lenalidomide and Rituximab (R2) Experimental Treatment 3 Interventions

Participants will receive epcoritamab in combination with R2 (ER2), followed by epcoritamab during the 120 week treatment duration.

Epcoritamab is already approved in United States, European Union for the following indications:

Approved in United States as Epkinly for:

• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy
• Diffuse large B-cell lymphoma after two or more lines of systemic therapy

Approved in European Union as Tepkinly for:

• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy
• Relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy

Who Is Running the Clinical Trial?

Genmab

Lead Sponsor

Trials

76

Recruited

15,300+

Dr. Jan van de Winkel

Genmab

Chief Executive Officer since 2010

PhD in Immunology, University of Utrecht

Dr. Judith Klimovsky

Genmab

Chief Medical Officer since 2019

MD, University of Copenhagen

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

Lenalidomide is an orally bioavailable immunomodulator that has shown significant antitumor activity in treating various types of B-cell lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma.

The drug has a favorable safety profile and is effective both as a standalone treatment and in combination with other therapies, marking a shift from traditional chemotherapy approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of lenalidomide in non-Hodgkin lymphoma. Galanina, N., Petrich, A., Nabhan, C.[2019]

In a phase II trial involving 66 patients with untreated follicular lymphoma, the combination of lenalidomide and rituximab achieved a high overall response rate of 95% and a complete response rate of 72%, indicating strong efficacy.

The treatment was associated with low rates of severe toxicity (grade 3-4), with a 5-year overall survival rate of 100%, suggesting that lenalidomide plus rituximab could be a safe and effective alternative to traditional chemotherapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Martin, P., Jung, SH., Pitcher, B., et al.[2023]

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

Epcoritamab is a bispecific antibody that targets CD3 and CD20, designed for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and received conditional approval in the USA on May 19, 2023, for adult patients after at least two prior therapies.

The drug has also received a positive opinion in the EU and is under review in Japan, indicating its potential as a significant treatment option for patients with difficult-to-treat B-cell non-Hodgkin lymphoma subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epcoritamab: First Approval. Frampton, JE.[2023]

Lenalidomide, especially when combined with rituximab (the 'R(2)' regimen), shows enhanced efficacy in treating indolent B-cell and mantle cell lymphomas, even in patients resistant to rituximab, while maintaining a manageable safety profile.

The most common serious side effect is asymptomatic neutropenia, which can be managed through dose adjustments, and while immune-related symptoms like rash are more frequent with the R(2) regimen, they are generally low-grade and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. Ruan, J., Shah, B., Martin, P., et al.[2020]

Lenalidomide, when used in combination with rituximab, has been shown to be an effective treatment for patients with relapsed or refractory follicular lymphoma, offering a chemotherapy-free option.

This combination therapy improves outcomes compared to using rituximab alone and may serve as a viable alternative to traditional chemoimmunotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in follicular lymphoma. Flowers, CR., Leonard, JP., Fowler, NH.[2021]

The combination of rituximab and lenalidomide (R2) significantly improves treatment efficacy for recurrent non-Hodgkin lymphoma compared to rituximab alone, leading to its approval for use in previously treated patients with follicular and marginal zone lymphoma.

R2 has a manageable safety profile, with common adverse events including grade 3/4 neutropenia, skin rashes, and gastrointestinal issues, indicating that while it is effective, careful monitoring and management of side effects are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. Cheson, BD., Morschhauser, F., Martin, P.[2021]

In a phase II trial involving 50 patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab, the combination of lenalidomide and rituximab resulted in a significant increase in overall response rate from 30.2% after lenalidomide alone to 62.8% after adding rituximab.

The median progression-free survival for patients receiving the lenalidomide-rituximab combination was 22.2 months, which was significantly longer than the 9.13 months observed with prior rituximab treatment, indicating that this combination can effectively overcome previous resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Chong, EA., Ahmadi, T., Aqui, NA., et al.[2022]

Lenalidomide is an FDA-approved immunomodulatory drug that shows strong efficacy in treating multiple myeloma and certain B-cell malignancies, particularly when combined with monoclonal antibodies like rituximab.

The drug works by modifying the tumor microenvironment and enhancing the activity of T and natural-killer (NK) cells, demonstrating excellent tolerability and potential to change treatment approaches for non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. Arora, M., Gowda, S., Tuscano, J.[2022]

Citations

1. onclive.com onclive.com/view/epcoritamab-plus-rituximab-and-lenalidomide-hits-both-primary-end-points-in-r-r-follicular-lymphoma

Epcoritamab Plus Rituximab and Lenalidomide Hits Both ... The epcoritamab, rituximab, and lenalidomide combination showed significant efficacy in relapsed/refractory follicular lymphoma, reducing death ...

2. news.abbvie.com news.abbvie.com/2025-09-03-AbbVie-Announces-Updated-Results-From-Phase-2-EPCORE-R-NHL-6-Study-Evaluating-the-Potential-for-Outpatient-Monitoring-of-Epcoritamab-in-Patients-With-Relapsed-Refractory-R-R-Diffuse-Large-B-Cell-Lymphoma-DLBCL

AbbVie Announces Updated Results From Phase 2 ... In follicular lymphoma the most common side effects of EPKINLY include injection site reactions, CRS, COVID-19, tiredness, upper respiratory ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05409066

NCT05409066 | Study of Subcutaneous Epcoritamab in ... This study will assess how safe and effective epcoritamab is in combination with lenalidomide and rituximab (R2) in treating adult participants with relapsed or ...

4. ashpublications.org ashpublications.org/blood/article-pdf/doi/10.1182/blood.2025029909/2411544/blood.2025029909.pdf

Fixed-Duration Epcoritamab Plus R2 Drives Favorable ... 4,5 In preclinical studies, lenalidomide has been shown to repair FL-induced T-cell dysfunction,6 and rituximab has been shown to promote antibody-dependent ...

5. appliedclinicaltrialsonline.com appliedclinicaltrialsonline.com/view/genmab-epkinly-major-survival-benefit-relapsed-refractory-follicular-lymphoma

Genmab's Epkinly Shows Major Survival Benefit in ... Epkinly combined with Rituxan and Revlimid significantly improves overall response rate and progression-free survival in relapsed or refractory ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04663347

NCT04663347 | Safety and Efficacy Trial of Epcoritamab ... The purpose of this trial is to measure the safety and effectiveness of epcoritamab (EPKINLY™), either by itself or together with other therapies, ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS7084

EPCORE FL-2: Phase 3 trial of epcoritamab with rituximab ... The objective of this trial is to evaluate the safety and efficacy of 1L epcoritamab plus R 2 vs CIT in patients with FL.

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4502.1/529091/Phase-3-Randomized-Open-Label-Study-of-Epcoritamab

Phase 3, Randomized, Open-Label Study of Epcoritamab Plus ... In the ongoing phase 1b/2 EPCORE NHL-5 study (NCT05283720), E-Len demonstrated high response rates (overall response rate, 18/24 [75.0%]; ...