Ibrutinib + Rituximab for Marginal Zone Lymphoma

Not currently recruiting at 14 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two treatments, ibrutinib (a type of cancer drug) and rituximab, can effectively treat marginal zone lymphoma in individuals who haven't tried any other treatment. Researchers will compare this combination to rituximab with a placebo to determine which works better. This trial might suit someone diagnosed with marginal zone lymphoma who has not yet received systemic (whole-body) treatment. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to developing a new treatment option.

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.

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

Research has shown that the combination of ibrutinib and rituximab is generally well-tolerated by patients with marginal zone lymphoma. Studies indicate that this treatment is usually safe, with most patients experiencing only mild to moderate side effects. Serious side effects occur less frequently and can be managed.

In another study, almost all patients responded positively to the treatment after 12 months. This finding suggests that the combination is not only effective but also safe for many people. While some side effects may occur, research supports the treatment's safety profile. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ibrutinib and Rituximab for treating Marginal Zone Lymphoma because it offers a fresh approach to tackling this type of cancer. While standard treatments often involve chemotherapy, Ibrutinib works differently by specifically targeting and inhibiting Bruton's tyrosine kinase (BTK), a key player in the growth and survival of cancer cells. When paired with Rituximab, a monoclonal antibody that targets the CD20 protein on B-cells, this combo may enhance the immune system's ability to fight the lymphoma more effectively than traditional therapies. This dual mechanism approach offers hope for improved outcomes with potentially fewer side effects compared to conventional chemotherapy.

What evidence suggests that the combination of ibrutinib and rituximab could be effective for marginal zone lymphoma?

Research has shown that using ibrutinib and rituximab together looks promising for treating marginal zone lymphoma. One study showed that this combination helped 97% of patients, with 53% experiencing a complete disappearance of their cancer. Another study found that 58% of patients responded well, with the benefits lasting a long time. In this trial, participants will receive either the combination of ibrutinib and rituximab or ibrutinib with a placebo. These findings suggest that combining ibrutinib and rituximab could be effective for people with this type of lymphoma. ^{2 6 7 8 9}

Who Is on the Research Team?

Ariela Noy, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

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

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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 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]

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]

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]

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 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]

Citations

1. jhoponline.com jhoponline.com/articles/imbruvica-ibrutinib-plus-rituxan-rituximab-new-combination-approved-for-the-treatment-of-waldenstroem-s-macroglobulinemia

Imbruvica (Ibrutinib) plus Rituxan (Rituximab) New ... This approval was based on the iNNOVATE study, which demonstrated improved outcomes when combining the targeted therapy ibrutinib plus immunotherapy with ...

2. hematologyadvisor.com hematologyadvisor.com/reports/marginal-zone-lymphoma-rituximab-ibrutinib-combination-treatment/

Rituximab and Ibrutinib Combination Shows Promise in ... Among patients who had data at the 12-month mark, the overall response rate (ORR) was 97%, with 53% of patients experiencing a complete response ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10835265/

Outcomes of marginal zone lymphoma treated with ... The final analysis of the study showed an ORR of 58% with durable responses. Comparable outcomes were seen with ibrutinib in R/R MZL in a real-world study as ...

4. targetedonc.com targetedonc.com/view/ibrutinib-combo-shows-improved-duration-of-response-in-rfl-mzl

Ibrutinib Combo Shows Improved Duration of Response in ... The combination of ibrutinib with chemoimmunotherapy improved the duration of response for a subset of patients with relapsed follicular lymphoma and marginal ...

5. jnj.com jnj.com/media-center/press-releases/phase-3-study-evaluating-imbruvica-ibrutinib-in-combination-with-rituximab-in-waldenstroms-macroglobulinemia-met-primary-endpoint

Phase 3 Study Evaluating IMBRUVICA® (ibrutinib) in ... Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37985359/

Safety and efficacy of ibrutinib in combination with rituximab ... Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: ...

7. ashpublications.org ashpublications.org/bloodadvances/article/8/3/549/506612/Outcomes-of-marginal-zone-lymphoma-treated-with

Outcomes of marginal zone lymphoma treated with ibrutinib in ... Outcomes of marginal zone lymphoma treated with ibrutinib in the first-line setting in the United States: a real-world analysis

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04212013?term=AREA%5BConditionSearch%5D(%22Marginal%20Zone%20Lymphoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22Enzyme%20Inhibitors%22)&rank=5

NCT04212013 | A Study of Ibrutinib With Rituximab in ... 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 ...

9. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/hon.3163_65

RITUXIMAB AND IBRUTINIB COMBINATION IS SAFE AND ... RITUXIMAB AND IBRUTINIB COMBINATION IS SAFE AND EFFECTIVE IN UNTREATED SPLENIC AND NODAL MARGINAL ZONE LYMPHOMAS: PLANNED SUBSET ANALYSIS OF THE ...