EZR for Follicular Lymphoma
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Reid Merryman, MD
Must not be taking: Immunosuppressants, Corticosteroids, Warfarin, CYP3A inducers
Disqualifiers: Autoimmune disease, Heart conditions, Infections, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
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)
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.
12345Is 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.
14678What 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.
29101112Eligibility 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
+8 more
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
+24 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Rituxam + Zanubrutinib + EpcoritamabExperimental Treatment3 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Dana-Farber Cancer InstituteBoston, MA
Brigham and Women's HospitalBoston, MA
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Who Is Running the Clinical Trial?
Reid Merryman, MDLead Sponsor
BeiGeneIndustry Sponsor
GenmabIndustry Sponsor
References
Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. [2022]Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. [2021]The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes.
How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? [2019]The outcome for patients with follicular lymphoma (FL) has substantially improved over the last few years. This improved survival appears to be largely related to the increasingly widespread use of anti-CD20 monoclonal antibody (mAb) rituximab in the therapy of FL today, either in combination with chemotherapy, for remission 'induction' and more recently as 'maintenance' therapy. Encouraging results have also been reported from radiolabelled anti-CD20 mAb or radioimmunotherapy (RIT), which exploits the unique method of action of this approach and high radiosensitivity of FL. High response rates and durable remissions have been seen with both (90)Y Ibritumomab tiuxetan and (131)I Tositumomab, and more recently compelling data are emerging demonstrating the efficacy of using these drugs as consolidation after initial treatment with chemotherapy or rituximab plus chemotherapy combinations. This review will focus on the current approaches and explore the data that has led to the emergence of a new nomenclature appearing in the language of clinicians involved in the treatment of FL, namely 'induction' therapy, 'consolidation' of initial response and 'maintenance' therapy. The current treatment approaches that have led to such increased optimism regarding the therapeutic outcome in FL are evaluated and discussed.
The combination of ibrutinib and rituximab demonstrates activity in first-line follicular lymphoma. [2021]This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once-daily ibrutinib 560 mg continuously plus once-weekly rituximab 375 mg/m2 for 4 weeks beginning Week 1 (Arm 1, n = 60) or Week 9 (following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n = 20). The primary endpoint was the best overall response rate (ORR). The median age was 58 years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73-93] and 75% (95% CI 51-91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30-month progression-free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first-line follicular lymphoma.
Biological therapy doublets: pairing rituximab with interferon, lenalidomide, and other biological agents in patients with follicular lymphoma. [2021]Rituximab (R) is a monoclonal antibody with high therapeutic efficacy in low-grade CD20+ lymphoma. The combination of R with chemotherapy is the most common treatment option for patients with follicular lymphoma (FL). The efficacy of R has also been shown to be augmented, when used in combinations with biologicals such as interferon-alpha-2a (IFN), bortezomib, or lenalidomide. The best combination of these drugs are not well defined and a better understanding of pharmacokinetics and timing of drugs relative to the rituximab infusion is crucial. Other new targeted agents, such as inhibitors of BTK and PI3Kdelta, have also been promising in FL. Translational research questions should be added to clinical trial protocols to increase the knowledge on how the tumor microenvironment and the host immune system affect the response to the different drugs and combinations with the aim of a more individualized therapy.
Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]Zanubrutinib (BGB-3111) is a next-generation Bruton tyrosine kinase inhibitor designed to be more selective with fewer off-target effects. We conducted a phase 1 study to assess the safety of its combination with obinutuzumab and evaluate early efficacy in 81 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or relapsed/refractory (R/R) follicular lymphoma (FL). In this phase 1b study, zanubrutinib was tolerable at 160 mg twice daily or 320 mg once daily combined with IV obinutuzumab in patients with CLL/SLL (n = 45) and FL (n = 36). Common adverse events (AEs) included upper respiratory tract infection (51%; n = 23), neutropenia (44%; n = 20), contusion (33%; n = 15), cough, diarrhea, or fatigue (27%; n = 12 each), and pyrexia (22%; n = 10) in CLL/SLL patients and upper respiratory tract infection (39%; n = 14), contusion (28%; n = 10), fatigue (25%; n = 9), and cough (22%; n = 8) in FL patients. Neutropenia was the most common grade 3/4 AE (CLL/SLL, 31% [n = 14]; FL, 14% [n = 5]). Five patients required temporary dose reductions, and 5 discontinued the study drug because of AEs. Overall response rate (ORR) was 100% (n = 20) in treatment-naïve CLL patients and 92% (n = 23) in R/R CLL patients. ORR in 36 R/R FL patients was 72% (n = 26), with 14 complete and 12 partial responses. Median follow-up was 29 months (range, 8-37) for CLL patients and 20 months (range, 2-37) for FL patients. Zanubrutinib and obinutuzumab combination therapy was generally well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02569476.
Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis - A cohort study. [2022]Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation.
Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin's lymphoma (B-NHL) chemotherapy: a meta-analysis. [2018]Rituximab is a monoclonal antibody targetting the CD20 antigen with the ability to increase overall remission (OR) in B-cell non-Hodgkin's lymphoma (B-NHL). A systematic review and meta-analysis were conducted to determine the risk of the most clinically relevant severe and fatal adverse events (AEs) associated with the use of rituximab in the treatment of B-NHL.
A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. [2021]Rituximab combined with chemotherapy has improved the survival of previously untreated patients with follicular lymphoma (FL). Nevertheless, many patients neither want nor can tolerate chemotherapy, leading to interest in biological approaches. Epratuzumab is a humanized anti-CD22 monoclonal antibody with efficacy in relapsed FL. Because both rituximab and epratuzumab have single-agent activity in FL, the antibody combination was evaluated as initial treatment of patients with FL.
Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. [2016]Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment.
Radioimmunotherapy in follicular lymphoma. [2019]The exquisite sensitivity of haematological malignancies to targeted radiation make Radioimmunotherapy (RIT) a theoretically attractive therapeutic approach. Furthermore, impressive results initially achieved by the pioneers in this field and more recently in larger studies have demonstrated the high clinical activity of RIT in follicular NHL (FL). For more than a decade clinical RIT of FL has been dominated by targeting the CD20 antigen and a number of pivotal clinical studies have resulted in the approval by the US FDA (Food and Drug Administration) of two radioimmunconjugates, (131)I-tositumomab (Bexxar) and (90)Y-ibritumomab (Zevalin). (90)Y-ibritumomab tiuxetan was subsequently approved within the EU in 2004 and more recently in the EU and in the US as a front line "consolidation" treatment in follicular NHL. Recent data have demonstrated that fractionated radioimmunotherapy targeting CD22 with (90)Y-epratuzumab tetraxetan achieved a high degree of durable complete responses in relapsed/refractory NHL. Despite the fact that these RIT agents clearly have unique non-cross reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab, they have not been widely adopted by haemato-oncology community to date. This chapter reviews the progress that has been made in the development of clinical radioimmunotherapy in follicular lymphoma and suggest some guidelines to use it appropriately in first-line but also in the increasing number of patients emerging who are rituximab-refractory.
Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma. [2022]Rituximab is an IgG1, chimeric monoclonal antibody specifically designed to recognize the CD20 antigen expressed on the surface of normal and malignant B-lymphocytes, from the B-cell precursor to the mature B-cells of the germinal center, and by most neoplasms derived from B-cells. After 2 decades of use, rituximab is firmly positioned in the treatment of follicular lymphoma (FL), both in the front line and in the relapsing disease, improving previous results by including it in classical chemotherapy regimens. However, the pharmacology of rituximab continues to generate controversial issues especially regarding the mechanisms of action in vivo. The contribution of rituximab as a maintenance treatment in FL has been significant progress in the management of this disease without an increase in side effects or a decrease in the quality of life of patients. With the widespread use of rituximab, there are new security alerts and side effects not previously detected in the pivotal trials that clinicians should learn to recognize and manage. In this article, we will review the pharmacokinetics and pharmacodynamics of rituximab, the management issues in the treatment of advanced FL focusing on maintenance rituximab, its long-term efficacy and safety profile, and its effect on the quality of life.