Tazemetostat + Zanubrutinib for Non-Hodgkin's Lymphoma

(TARZAN Trial)

Overseen By Narendranath Epperla

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Myeloid malignancies, T-LBL, T-ALL, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 8 months

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining Tazemetostat with Zanubrutinib and an anti-CD20 monoclonal antibody is a safe and effective treatment for certain types of non-Hodgkin's lymphoma. It targets patients whose cancer has returned or did not respond to previous treatments. Candidates for this trial include those previously treated for non-Hodgkin's lymphoma who require further treatment due to active disease. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires a 'washout' period (time without taking certain medications) for some treatments before starting the study drugs. If you are taking strong or moderate CYP3A inducers or inhibitors, you may need to stop them before joining the trial. It's best to discuss your current medications with the trial team to see if any changes are needed.

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

Studies have shown that tazemetostat, when used alone, generally maintains a good safety record. However, some patients experienced treatment-related side effects, with about 13.6% facing more serious ones, mostly affecting the blood. Zanubrutinib is also known for being safe and well-tolerated when used independently.

This trial tests these two drugs together with an anti-CD20 monoclonal antibody, a type of targeted therapy. While researchers continue to study this combination, each drug has been used before and is generally well-tolerated. This suggests the treatment might be reasonably safe, but it is important to remember that this is an early-stage trial. Such trials often focus on determining the right dose and checking for any early signs of safety issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tazemetostat combined with Zanubrutinib for treating Non-Hodgkin's Lymphoma because this combo targets the disease in a novel way. Unlike standard treatments that mainly focus on destroying cancer cells with chemotherapy or using monoclonal antibodies like Rituximab and Obinutuzumab, Tazemetostat inhibits EZH2, an enzyme that plays a role in cancer cell growth. Zanubrutinib, on the other hand, is a Bruton’s tyrosine kinase (BTK) inhibitor, which blocks signals that help cancer cells survive. This dual approach could offer a more effective way to halt cancer progression by simultaneously attacking different pathways critical for cancer cell survival.

What evidence suggests that this trial's treatments could be effective for non-Hodgkin's lymphoma?

Research has shown that Tazemetostat holds promise for patients with relapsed or hard-to-treat B-cell non-Hodgkin lymphoma by shrinking tumors and delaying cancer progression. Zanubrutinib, another key drug in this trial, has also yielded positive results. Specifically, studies found that patients taking Zanubrutinib experienced about 10.4 months without cancer progression. This trial will explore the combination of Tazemetostat and Zanubrutinib with an anti-CD20 monoclonal antibody, a protein that targets cancer cells, aiming to enhance these effects and improve patient outcomes. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for individuals with indolent B-cell non-Hodgkin lymphoma that has come back or hasn't responded to treatment. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and have a confirmed diagnosis.

Inclusion Criteria

Ability to read, understand, and provide informed consent

Life expectancy of >3 months

Compliance with requirements and restrictions listed in the informed consent form and protocol

Exclusion Criteria

Positive for HIV, active HBV or HCV infection, CMV infection

I don't have major GI issues, recent surgeries, or active bleeding problems.

I do not have severe liver disease, brain involvement, or heart rhythm issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Tazemetostat in combination with Zanubrutinib and anti-CD20 monoclonal antibody to determine the Maximum Tolerated Dose (MTD)

8 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of Progression-Free Survival (PFS) and Overall Survival (OS)

2 years

Long-term Follow-up

Participants are monitored for long-term outcomes such as Median Duration of Response (DOR) and Overall Survival (OS)

7 years

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Rituximab
• Tazemetostat
• Zanubrutinib

Trial Overview The study is testing the safety and effectiveness of Tazemetostat in combination with Zanubrutinib and anti-CD20 monoclonal antibodies (Rituximab or Obinutuzumab) for treating relapsed or refractory indolent B-cell non-Hodgkin lymphoma.

How Is the Trial Designed?

Group I: Treatment: All Patients Experimental Treatment 4 Interventions

The study will investigate the effectiveness of Tazemetostat in combination with Zanubrutinib and anti-CD20 monoclonal antibody

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

In a phase II study involving 217 patients with relapsed/refractory follicular lymphoma, the combination of zanubrutinib and obinutuzumab (ZO) showed a significantly higher overall response rate (ORR) of 69% compared to 46% for obinutuzumab alone, indicating greater efficacy.

The safety profile of ZO was manageable, with common side effects including thrombocytopenia and neutropenia, and serious adverse events like atrial fibrillation occurring in only 3% of patients, suggesting that ZO could be a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. Zinzani, PL., Mayer, J., Flowers, CR., et al.[2023]

The Phase III GADOLIN trial showed that obinutuzumab combined with bendamustine significantly improves progression-free survival in patients with rituximab-refractory indolent non-Hodgkin lymphoma compared to bendamustine alone.

Obinutuzumab has received FDA approval for treating follicular lymphoma that has relapsed or is refractory to rituximab, highlighting its efficacy in a challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab for the treatment of indolent lymphoma. Edelmann, J., Gribben, JG.[2018]

Obinutuzumab, combined with bendamustine, significantly prolonged progression-free survival (PFS) in patients with indolent non-Hodgkin's lymphoma, particularly benefiting those with follicular lymphoma, as shown in the phase III GADOLIN study.

The treatment was generally well-tolerated, with mild to moderate infusion-related reactions being the most common side effects, while neutropenia was the most frequent severe adverse event, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma. Dhillon, S.[2018]

The combination of obinutuzumab and atezolizumab was found to be safe and tolerable in a phase 1b study involving 49 patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), with no new toxicities reported.

The treatment showed preliminary efficacy, achieving a 54% objective response rate in the FL cohort and a 17% response rate in the DLBCL cohort, with median progression-free survival of 9 months for FL and 3 months for DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study. Palomba, ML., Till, BG., Park, SI., et al.[2022]

Obinutuzumab, a novel CD20 antibody, demonstrated superior anti-tumor activity compared to rituximab in preclinical mouse models of non-Hodgkin lymphoma, particularly when combined with chemotherapy agents like bendamustine.

In these studies, obinutuzumab alone was at least as effective as rituximab combined with chemotherapy, suggesting it could be a more effective treatment option for patients with non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma. Herting, F., Friess, T., Bader, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06824701

Study Details | NCT06824701 | Tazemetostat in ... VGPR is a treatment outcome for t B-cell non-Hodgkin lymphomas characterized by detectable monoclonal IgM protein, ≥90% reduction in serum IgM level from ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT05890352

A Phase 2 Study Adding the Drugs Tazemetostat or ... The addition of tazemetostat or zanubrutinib to usual treatment with tafasitamab and lenalidomide may be able to shrink cancer or extend the time without cancer ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9198905/

Zanubrutinib monotherapy in relapsed/refractory indolent non ... 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 ...

4. withpower.com withpower.com/trial/phase-1-lymphoma-6-2023-7a391

Tazemetostat + CAR T Therapy for Non-Hodgkin's ... Research shows that Tazemetostat has demonstrated promising results in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, especially those with ...

5. onclive.com onclive.com/view/tazemetostat-displays-promising-preclinical-activity-in-btk-resistant-mcl-cell-lines

Tazemetostat Displays Promising Preclinical Activity in ... In the present study, in vivo studies demonstrated a significant prolongation in the time to tumor growth with the combination of tazemetostat ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12391435/

Efficacy and safety of tazemetostat, an EZH2 inhibitor, in ... In a global study (NCT01897571), tazemetostat monotherapy showed antitumour activity and a favourable safety profile in patients with relapsed or refractory ...

7. researchgate.net researchgate.net/publication/395151781_Efficacy_and_safety_of_tazemetostat_an_EZH2_inhibitor_in_Chinese_patients_with_relapsedrefractory_follicular_lymphoma_a_multicentre_single-arm_phase_2_study

Efficacy and safety of tazemetostat, an EZH2 inhibitor, in ... All patients experienced treatment-related adverse events (TRAEs), and 13.6% had grade ≥3 TRAEs; most common TRAEs were haematological ...

8. ashpublications.org ashpublications.org/bloodadvances/article/6/11/3472/484634/Zanubrutinib-monotherapy-in-relapsed-refractory

Zanubrutinib monotherapy in relapsed/refractory indolent non ... Zanubrutinib is a second-generation Bruton's tyrosine kinase inhibitor with a favorable safety and tolerability profile.