Ibrutinib + Rituximab for Marginal Zone Lymphoma

Recruiting at 13 trial locations

Overseen By M. Lia Palomba, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Strong CYP3A inhibitors, Immunosuppressants

Disqualifiers: CNS lymphoma, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

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

Compensation: Varies

Number of Visits: 4

Duration: 28-day cycles

23 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 need continuous treatment with strong CYP3A inhibitors or are on systemic immunosuppressant therapy within 28 days of starting the study drug.

What data supports the effectiveness of the drug combination Ibrutinib and Rituximab for treating Marginal Zone Lymphoma?

Research shows that the combination of Ibrutinib and Rituximab is effective in treating other types of lymphomas, such as follicular lymphoma, with high response rates and good tolerance. Additionally, Ibrutinib has shown activity in various lymphomas, suggesting potential effectiveness in Marginal Zone Lymphoma as well. ^{1 2 3 4 5}

Is the combination of Ibrutinib and Rituximab generally safe for humans?

The combination of Ibrutinib and Rituximab has been studied in various conditions and is generally considered tolerable, with common side effects including fatigue, diarrhea, and nausea. Serious blood, bleeding, and heart-related side effects are less common. ^{1 2 5 6 7}

How is the drug combination of Ibrutinib and Rituximab unique for treating marginal zone lymphoma?

The combination of Ibrutinib and Rituximab is unique for treating marginal zone lymphoma because it targets B-cell receptor signaling, which is often linked to the disease, and offers a chemotherapy-free option. Ibrutinib inhibits Bruton tyrosine kinase, while Rituximab targets the CD20 antigen on B cells, enhancing their clearance. ^{1 8 9 10 11}

What is the purpose of this trial?

The purpose of this study is to see if the combination of rituximab and ibrutinib can help people with marginal zone lymphoma who have not received treatment in the past. The study will also compare the combination of rituximab and ibrutinib with the combination of rituximab and placebo to see which combination works better.

Research Team

Ariela Noy, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with untreated marginal zone lymphoma, including splenic, nodal, and extranodal types. They must have a life expectancy over 3 months and be able to perform daily activities with slight limitations (ECOG ≤2). Women of childbearing potential need a negative pregnancy test and agree to use birth control. Participants should not have severe heart conditions, bleeding disorders, central nervous system lymphoma or other serious health issues that could affect the study.

Inclusion Criteria

I agree to use effective birth control during and after the study.

My lymphoma type is confirmed as marginal zone lymphoma.

I have gastric MALT lymphoma, am H. pylori negative or didn't respond to treatment, and can't or won't have gastric radiation.

Exclusion Criteria

I have been screened for hepatitis B and C, and if positive for HBV, I am on appropriate treatment.

Human immunodeficiency virus (HIV): NOTE: HIV is a contraindication if the subject has an active opportunistic infection (OI) within 12 months and CD4 count is below the normal range

I have no cancer history except for certain skin cancers or cancers treated over 2 years ago with no current signs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rituximab and ibrutinib or rituximab and placebo

28-day cycles

4 visits (in-person) during cycle 1

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 months

Treatment Details

Interventions

• Ibrutinib
• Placebo
• Rituximab

Trial Overview The study tests if rituximab combined with ibrutinib is more effective than rituximab with a placebo in treating marginal zone lymphoma. Patients are randomly assigned to either the drug combo or the placebo group to compare outcomes.

Participant Groups

Group I: Ibrutinib/Rituximab Experimental Treatment 2 Interventions

All subjects meeting eligibility criteria will receive rituximab: 375 mg/m\^2 on days 1, 8, 15 and 22 on cycle 1.

Group II: Ibrutinib/Placebo Placebo Group 2 Interventions

Ibrutinib capsules (140 mg each) will be dosed at 560 mg once daily on a 28-day cycle on a continuous basis. Placebo capsules will be similarly dosed at 4 capsules daily.

Ibrutinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in United States as Imbruvica for:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma
• Graft-versus-host disease

Approved in Canada as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia
• Marginal zone lymphoma

Approved in Japan as Imbruvica for:

• Chronic lymphocytic leukemia
• Mantle cell lymphoma
• Waldenström's macroglobulinemia

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Findings from Research

In a study of 838 patients with untreated non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), the combination of ibrutinib and R-CHOP did not improve event-free survival (EFS) for the overall population, but showed significant benefits for patients under 60 years old, improving EFS, progression-free survival (PFS), and overall survival (OS).

For patients aged 60 and older, the combination treatment worsened EFS, PFS, and OS, increased serious adverse events, and reduced the number of patients able to complete the full R-CHOP regimen, indicating that age significantly influences the safety and efficacy of ibrutinib in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. Younes, A., Sehn, LH., Johnson, P., 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]

Novel agents like lenalidomide, bortezomib, and 90yttrium-ibrutumomab tiuxetan have shown efficacy in treating marginal zone lymphoma, based on trials specifically designed for this patient group.

Targeted therapies such as obinutuzumab, ibrutinib, and idelalisib, along with newer drugs like venetoclax and copanlisib, are being explored for their safety and effectiveness, indicating a promising direction for treatment in indolent non-Hodgkin's lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible novel agents in marginal zone lymphoma. Zinzani, PL., Broccoli, A.[2021]

In a phase 2 trial involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib, lenalidomide, and rituximab resulted in a high overall response rate of 76%, with 56% achieving a complete response, suggesting this triplet therapy is effective.

While the treatment showed promising efficacy, it was associated with significant adverse events, including neutropenia in 38% of patients and three treatment-related deaths, highlighting the need for careful monitoring and further evaluation in randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Jerkeman, M., Eskelund, CW., Hutchings, M., et al.[2022]

In the HELIOS trial involving 578 subjects, the combination of bendamustine/rituximab and ibrutinib (BR-I) resulted in significantly higher systemic exposure to rituximab compared to bendamustine/rituximab with placebo (BR), particularly in the initial treatment cycles.

The study found no significant safety differences between the BR-I and BR groups, suggesting that the enhanced efficacy of BR-I may be achieved without compromising patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Lavezzi, SM., de Jong, J., Neyens, M., et al.[2021]

In a study of 31 patients with rituximab-refractory Waldenström's macroglobulinaemia, ibrutinib demonstrated a high overall response rate of 90%, with 71% achieving a major response, indicating its efficacy as a treatment option for this difficult-to-treat population.

The treatment also showed a favorable safety profile, with manageable adverse effects, and significant improvements in hemoglobin levels and quality of life measures, suggesting that ibrutinib could be a viable chemotherapy-free alternative for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Dimopoulos, MA., Trotman, J., Tedeschi, A., et al.[2022]

The combination of rituximab and ibrutinib in a 57-year-old patient with mantle cell lymphoma led to a severe disseminated enterovirus infection, highlighting the significant risk of immunodeficiency and severe immune-related side effects from this treatment regimen.

High-dose intravenous immunoglobulins were effective in clearing the virus and restoring organ function, suggesting that this treatment should be considered for patients experiencing severe enterovirus infections while on rituximab and ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. Higer, M., Cana, D., Podlech, J., et al.[2021]

In a phase II study involving 50 previously untreated patients with indolent mantle cell lymphoma (MCL), the combination of ibrutinib and rituximab resulted in an impressive 80% complete response rate after 12 treatment cycles.

The treatment also led to undetectable minimal residual disease (MRD) in 87% of patients, allowing 69% of evaluable patients to safely discontinue ibrutinib after 2 years, although caution is advised for those with TP53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial. Giné, E., de la Cruz, F., Jiménez Ubieto, A., et al.[2022]

In a phase 1b study involving 33 patients with untreated CD20-positive B-cell non-Hodgkin lymphoma, the combination of ibrutinib and R-CHOP was found to be well tolerated, with a recommended dose of 560 mg per day for ibrutinib, and a high overall response rate of 94% among those treated.

The study indicated that ibrutinib did not interfere with the pharmacokinetics of R-CHOP components, suggesting a safe combination therapy that could enhance treatment responses, particularly in patients with different subtypes of diffuse large B-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Younes, A., Thieblemont, C., Morschhauser, F., et al.[2021]

References

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

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. [2022]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

Possible novel agents in marginal zone lymphoma. [2021]

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

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. [2022]

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

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]

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

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. [2022]

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

Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. [2021]

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

Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. [2021]