Tazemetostat + Zanubrutinib for Non-Hodgkin's Lymphoma

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

Trial Summary

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.

What data supports the effectiveness of the drug combination Tazemetostat + Zanubrutinib for Non-Hodgkin's Lymphoma?

Research shows that the combination of zanubrutinib and obinutuzumab was effective in treating relapsed or refractory follicular lymphoma, a type of non-Hodgkin's lymphoma. Additionally, obinutuzumab has been shown to improve progression-free survival in patients with follicular lymphoma when combined with chemotherapy. ^{1 2 3 4 5}

What safety data exists for Tazemetostat + Zanubrutinib in Non-Hodgkin's Lymphoma?

Obinutuzumab, a drug similar to those in the trial, has been associated with increased risks of serious infections, infusion reactions, and heart issues. These findings suggest that while effective, the treatment may come with significant side effects. ^{1 2 4 6 7}

How is the drug combination of Tazemetostat and Zanubrutinib unique for treating Non-Hodgkin's Lymphoma?

The combination of Tazemetostat and Zanubrutinib for Non-Hodgkin's Lymphoma is unique because it combines a targeted therapy (Tazemetostat) that inhibits a specific enzyme involved in cancer cell growth with a Bruton tyrosine kinase inhibitor (Zanubrutinib) that blocks signals needed for cancer cell survival, potentially offering a novel approach for patients who have relapsed or are resistant to other treatments. ^{2 4 5 8 9}

What is the purpose of this trial?

The purpose of this clinical trial is to learn if the study drug Tazemetostat combined with Zanubrutinib and anti-CD20 monoclonal antibody is safe and effective in treating patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

1. United States 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. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Obinutuzumab for the treatment of indolent lymphoma. [2018]

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

Obinutuzumab Effective in Follicular Lymphoma, but at a Cost. [2018]

4. United States 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. [2023]

5. France pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

Obinutuzumab-related adverse events: A systematic review and meta-analysis. [2021]

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

Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. [2022]

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

Factors associated with toxicity and response to yttrium 90-labeled ibritumomab tiuxetan in patients with indolent non-Hodgkin's lymphoma. [2019]

9. United States 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. [2022]