EZR for Follicular Lymphoma

Recruiting at 2 trial locations

Overseen By Heather A Walker, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Reid Merryman, MD

Must not be taking: Immunosuppressants, Corticosteroids, Warfarin, CYP3A inducers

Disqualifiers: Autoimmune disease, Heart conditions, Infections, others

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

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

Compensation: Varies

Number of Visits: 11

Duration: 24 months

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of three drugs—epcoritamab (also known as Epkinly or Tepkinly), zanubrutinib (known as Brukinsa), and rituximab—can effectively and safely treat people with follicular lymphoma (FL) or marginal zone lymphoma (MZL) that has returned or not responded to past treatments. Participants will receive these drugs for up to a year and attend follow-up visits for up to 10 years to monitor results. Ideal participants are those previously treated for FL or MZL who still have measurable disease, meaning noticeable signs of cancer in their body that can be measured through medical imaging. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require certain medications like strong CYP3A inducers or warfarin. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research shows that the combination of epcoritamab, zanubrutinib, and rituximab is being tested for safety in treating follicular lymphoma (FL) and marginal zone lymphoma (MZL). Previous studies have demonstrated that epcoritamab, when combined with other drugs, led to a complete response in many patients, meaning their cancer disappeared. The FDA has already approved zanubrutinib for use with other drugs in similar conditions, indicating it is generally well-tolerated.

Rituximab is a common treatment and is generally considered safe. Its combination with zanubrutinib has been tested in patients with similar types of lymphoma, showing promising safety results.

These treatments remain under study, but their presence in a phase 2 trial indicates earlier tests found them safe enough to continue research. This suggests no serious safety concerns have arisen so far. However, like any treatment, side effects can occur, and discussing these with the study team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Epcoritamab, Rituximab, and Zanubrutinib for follicular lymphoma because it brings a novel approach to treatment. Unlike the standard of care, which typically involves chemotherapy and monoclonal antibodies like Rituximab alone, this combination introduces Epcoritamab, a bispecific antibody that targets both CD3 and CD20, potentially enhancing the immune system's ability to attack cancer cells. Additionally, Zanubrutinib is a newer Bruton’s tyrosine kinase (BTK) inhibitor, offering a more targeted attack on cancer cell growth and survival pathways. This combination aims to improve effectiveness and reduce reliance on traditional chemotherapy, which comes with significant side effects.

What evidence suggests that this trial's treatments could be effective for Follicular Lymphoma or Marginal Zone Lymphoma?

This trial will evaluate the combination of three drugs—epcoritamab, zanubrutinib, and rituximab—to treat follicular lymphoma (FL) and marginal zone lymphoma (MZL). Research has shown promising results for similar combinations in previous studies, where patients with these lymphomas that had returned or were unresponsive to other treatments showed high response rates and significant remission. Epcoritamab helps the immune system find and attack cancer cells. Zanubrutinib blocks signals that promote cancer cell growth. Rituximab has been effective in helping patients live longer by directly attacking certain lymphoma cells. This drug combination in the trial aims to enhance the body's ability to fight these specific types of lymphoma. ^{1 2 5 6 7}

Who Is on the Research Team?

Reid W Merryman, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for individuals with Follicular Lymphoma that has returned or hasn't responded to previous treatments. Participants should meet specific health criteria set by the study, but these details are not provided here.

Inclusion Criteria

Ability to understand and sign a written informed consent document

Willingness to provide a pre-treatment tumor sample

My blood counts and organ functions are within normal ranges.

Exclusion Criteria

I have large neck lymph nodes affecting my breathing.

I cannot tolerate anti-CD20 therapy or am allergic to epcoritamab.

Presence of HCV antibody unless HCV RNA undetectable

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive epcoritamab, zanubrutinib, and rituximab for up to 24 months

24 months

In-clinic visits with imaging on cycles 3, 6, 9, 13, and 19

End of Treatment

End of Treatment visit with imaging and bone marrow biopsy

4 weeks after cycle 24 day 1

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness every 6 months for up to 10 years

10 years

Follow-up visits every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Epcoritamab
• Rituximab
• Zanubrutinib

Trial Overview The trial tests a combination of three drugs: Epcoritamab (antibody), Zanubrutinib (Bruton tyrosine kinase inhibitor), and Rituximab (monoclonal antibody) to see how effective and safe they are in treating relapsed or refractory Follicular Lymphoma.

How Is the Trial Designed?

Group I: Rituxan + Zanubrutinib + Epcoritamab for MZL Experimental Treatment 3 Interventions

Enrolled participants will complete: * Baseline visit with imaging and bone marrow biopsy * Imaging on cycles 3, 6, 9 * Up to 1 year of treatment with study drugs * End of Treatment visit with imaging and bone marrow biopsy * Follow up visits every 6 months for up to 10 years

Group II: Rituxan + Zanubrutinib + Epcoritamab for FL Experimental Treatment 3 Interventions

Enrolled participants will complete: * Baseline visit with imaging and bone marrow biopsy * Imaging on cycles 3, 6, 9 * Up to 1 year of treatment with study drugs * End of Treatment visit with imaging and bone marrow biopsy * Follow up visits every 6 months for up to 10 years

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?

Reid Merryman, MD

Lead Sponsor

Trials

3

Recruited

110+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Genmab

Industry 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

Published Research Related to This Trial

The combination of epratuzumab and rituximab was well-tolerated in 59 untreated patients with follicular lymphoma, showing a high response rate of 88.2%, with 42.4% achieving complete responses.

At a 3-year follow-up, 60% of patients remained in remission, indicating that this non-chemotherapy approach can provide effective long-term outcomes similar to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Grant, BW., Jung, SH., Johnson, JL., et al.[2021]

In a study of 60 patients with symptomatic or bulky follicular lymphoma, a combination of short-course chemoimmunotherapy (CHOP-R) followed by radioimmunotherapy (RIT) led to a significant increase in complete response (CR) rates, from 40% after CHOP-R to 82% after RIT, as assessed by imaging.

The study found that patients who did not achieve a complete metabolic response on PET imaging after CHOP-R had a higher risk of relapse, highlighting the importance of early PET assessment in predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Jacobs, SA., Swerdlow, SH., Kant, J., et al.[2016]

In a study of 53 patients with relapsed/refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL), the selective Bruton's tyrosine kinase inhibitor zanubrutinib showed an overall response rate of 80% for MZL and 36.4% for FL, indicating significant efficacy in these difficult-to-treat cancers.

Zanubrutinib was generally well tolerated, with most adverse events being mild (≤ grade 2), and no reports of atrial fibrillation/flutter, suggesting a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. Phillips, T., Chan, H., Tam, CS., et al.[2022]

In a phase 2 study involving 80 adults with untreated follicular lymphoma, the combination of ibrutinib and rituximab showed a high overall response rate of 85% in the first treatment arm and 75% in the second arm, indicating strong efficacy.

The treatment was generally well-tolerated, with common side effects including fatigue, diarrhea, and nausea, while serious adverse events were rare, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. Fowler, NH., Nastoupil, L., De Vos, S., et al.[2021]

Radioimmunotherapy (RIT) has shown high clinical efficacy in treating follicular non-Hodgkin lymphoma (NHL), particularly with agents targeting the CD20 antigen, leading to FDA approvals for (131)I-tositumomab and (90)Y-ibritumomab.

Recent studies indicate that targeting CD22 with (90)Y-epratuzumab tetraxetan can achieve durable complete responses in patients with relapsed or refractory NHL, although these therapies have not yet been widely adopted in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radioimmunotherapy in follicular lymphoma. Illidge, T., Morschhauser, F.[2019]

In a study of patients with newly-diagnosed low-tumor-burden follicular lymphoma, certain genetic profiles (KIR2DL2 with HLA-C1 and KIR3DL1 with HLA-Bw4) were associated with improved outcomes when receiving maintenance rituximab treatment, suggesting a potential biomarker for treatment efficacy.

The findings indicate that the effectiveness of rituximab, a tumor-reactive monoclonal antibody, may be influenced by the genetic makeup of patients, particularly the KIR/KIR-ligand interactions on natural killer cells, although further validation in independent studies is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. Erbe, AK., Wang, W., Carmichael, L., et al.[2021]

The use of the anti-CD20 monoclonal antibody rituximab has significantly improved survival rates in patients with follicular lymphoma (FL), especially when used in combination with chemotherapy for both induction and maintenance therapy.

Radioimmunotherapy (RIT) using radiolabelled anti-CD20 mAbs, such as (90)Y Ibritumomab tiuxetan and (131)I Tositumomab, has shown high response rates and durable remissions, particularly when used as consolidation therapy after initial treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? Illidge, T., Chan, C.[2019]

Rituximab is an effective treatment for follicular lymphoma (FL), improving outcomes when used in combination with traditional chemotherapy, and has shown significant benefits as a maintenance therapy without increasing side effects or compromising patients' quality of life.

Despite its long history of use, new safety alerts and side effects have emerged that clinicians need to be aware of, highlighting the importance of ongoing monitoring and management in patients receiving rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma. Aguiar-Bujanda, D., Blanco-Sánchez, MJ., Hernández-Sosa, M., et al.[2022]

Rituximab is highly effective for treating low-grade CD20+ lymphoma, especially when combined with chemotherapy, which is the standard treatment for follicular lymphoma (FL).

The efficacy of rituximab can be enhanced by combining it with biological agents like interferon-alpha-2a, bortezomib, or lenalidomide, but more research is needed to determine the best combinations and timing of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. Kimby, E.[2021]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, was found to be generally well tolerated when combined with obinutuzumab in a phase 1 study involving 81 patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

The combination therapy showed high efficacy, achieving a 100% overall response rate in treatment-naïve CLL patients and a 92% response rate in relapsed/refractory CLL patients, with a 72% response rate in relapsed/refractory FL patients over a median follow-up of 20 to 29 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Tam, CS., Quach, H., Nicol, A., et al.[2021]

Rituximab, a monoclonal antibody used in treating B-cell non-Hodgkin's lymphoma, does not significantly increase the risk of most severe adverse events compared to chemotherapy alone, based on a meta-analysis of eight clinical trials.

However, there is a notable increase in the risk of fatal adverse events, particularly infections, in patients receiving rituximab, indicating a need for further investigation into its safety profile regarding infection-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin's lymphoma (B-NHL) chemotherapy: a meta-analysis. Hua, Q., Zhu, Y., Liu, H.[2018]

In a study of 365 multiple sclerosis patients treated with rituximab over four years, the treatment showed a very low annualized relapse rate (ARR) of 0.03, indicating high efficacy in preventing disease relapses.

While rituximab was generally safe, with 79% of patients achieving no evidence of disease activity (NEDA-3), there were notable risks of infections and neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis - A cohort study. Torgauten, HM., Myhr, KM., Wergeland, S., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06563596

NCT06563596 | Epco, Zanu, Ritux for R/R FL or MZL The purpose of this study is to determine how effective and safe the combination of epcoritamab, zanubrutinib, and rituximab is in treating participants ...

2. dana-farber.org dana-farber.org/clinical-trials/24-393

A Phase 2 Study of Epcoritamab, Zanubrutinib, and ... The purpose of this study is to determine how effective and safe the combination of epcoritamab, zanubrutinib, and rituximab is in treating participants ...

3. ashpublications.org ashpublications.org/blood/article/146/15/1802/535795/End-points-and-outcomes-in-follicular-lymphoma

End points and outcomes in follicular lymphoma: what should ... Overall survival (OS) and quality of life (QoL) are clinically relevant outcomes/end points during examination of therapies.

4. sciencedirect.com sciencedirect.com/science/article/pii/S000649712501938X

Treatment of relapsed and refractory follicular lymphoma The GADOLIN study demonstrated improved OS with obinutuzumab plus bendamustine followed by obinutuzumab maintenance over bendamustine alone in ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12167646/

Follicular Lymphoma: Current Therapeutic Landscape and ... First‐line immunochemotherapy achieves excellent long‐term outcomes, for example, 10‐year progression‐free survival (PFS) at 35%–51% and OS at ...

6. ashpublications.org ashpublications.org/blood/article/146/15/1782/546730/Treatment-of-relapsed-and-refractory-follicular

Treatment of relapsed and refractory follicular lymphoma Available data suggest that high-risk features like double-refractory status, POD24, or rituximab refractoriness do not significantly impact the ...

7. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/bjh.70126

Towards a chemo‐free approach for follicular lymphoma Recent results from the phase I/II EPCORE NHL-2 trial showed that epcoritamab–rituximab–lenalidomide achieved 98% ORR, with an 87% CR rate in RR ...