EZR for Follicular Lymphoma

Recruiting at 1 trial location

Overseen By Reid Merryman, MD

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

24 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination for follicular lymphoma?

Research shows that rituximab, a key component of the treatment, has significantly improved outcomes for follicular lymphoma patients, especially when used with chemotherapy or other biological agents. Additionally, zanubrutinib, another component, has shown a favorable response in patients with relapsed or difficult-to-treat follicular lymphoma. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Zanubrutinib, used in treating follicular lymphoma, was generally well tolerated with most side effects being mild. Rituximab, another treatment option, has been associated with some severe side effects, but these are not common. Overall, these treatments have shown a favorable safety profile in clinical studies. ^{1 4 6 7 8}

What makes the drug EZR (Epcoritamab, Rituximab, Zanubrutinib) unique for treating follicular lymphoma?

The drug EZR combines Epcoritamab, a bispecific antibody that targets both CD3 on T-cells and CD20 on B-cells, with Rituximab and Zanubrutinib, offering a novel approach by engaging the immune system more directly compared to traditional chemotherapy. This combination may provide an alternative for patients who cannot tolerate chemotherapy, leveraging the unique mechanisms of each component to potentially enhance treatment efficacy. ^{2 9 10 11 12}

What is the purpose of this trial?

The purpose of this study is to determine how effective and safe the combination of epcoritamab, zanubrutinib, and rituximab is in treating participants with relapse or refractory Follicular Lymphoma (FL). * The names of the study drugs involved in this research study are: * Epcoritamab (a type of antibody) * Zanubrutinib (a type of Bruton tyrosine kinase inhibitor) * Rituximab (a type of monoclonal antibody)

Research Team

Reid W Merryman, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

My blood counts and organ functions are within normal ranges.

Ability to understand and sign a written informed consent document

Willingness to provide a pre-treatment tumor sample

Exclusion Criteria

I have large neck lymph nodes affecting my breathing.

I don't need ongoing immune system suppression medication, except for short-term steroids.

Presence of HCV antibody unless HCV RNA undetectable

Timeline

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

Treatment Details

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.

Participant Groups

Group I: Rituxam + Zanubrutinib + Epcoritamab Experimental Treatment 3 Interventions

Enrolled participants will complete: * Baseline visit with imaging and bone marrow biopsy * Imaging on cycles 3, 6, 9, 13, and 19 * Up to 2 years 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

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. [2022]

2. England 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. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? [2019]

4. England pubmed.ncbi.nlm.nih.gov

The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

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

6. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis - A cohort study. [2022]

8. England 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. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. [2021]

10. United States 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. [2016]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Radioimmunotherapy in follicular lymphoma. [2019]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma. [2022]