Combination Therapy for Lymphoma

Recruiting at 5 trial locations

Overseen By Annette Hay

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Canadian Cancer Trials Group

Must be taking: Methotrexate, Ibrutinib, Rituximab

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Secondary CNS NHL, Active infections, others

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

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: Up to 2 years

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to answer the following question: Can the addition of a new drug to the usual treatment lower the chance of primary central nervous system lymphoma growing or spreading? This study is being done to find out if this approach is better or worse than the usual approach for this type of cancer. The usual approach is defined as the care most people get for Primary Central Nervous System Lymphoma (PCNSL).

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as anticoagulants like warfarin, strong CYP3A inhibitors or inducers, and corticosteroids above a certain dose. You should also avoid supplements with fish oil or vitamin E, and grapefruit juice. Please consult with your doctor to review your current medications.

What safety data exists for the combination therapy of Ibrutinib and Rituximab?

The combination of Ibrutinib and Rituximab has been studied for safety in various types of lymphoma. Common side effects include fatigue, diarrhea, and nausea, while more serious blood, bleeding, and heart-related issues are less frequent. Rituximab can also cause a weakened immune system, which may lead to infections. ^{1 2 3 4 5}

What makes the combination therapy of Ibrutinib, Methotrexate, and Rituximab unique for treating lymphoma?

This combination therapy is unique because it combines Ibrutinib, which inhibits a protein important for B-cell activity, with Rituximab, which targets and helps clear B-cells, and Methotrexate, a chemotherapy drug, to potentially enhance treatment effectiveness compared to using these drugs separately. ^{2 4 5 6 7}

Research Team

Jean-Francois Larouche

Principal Investigator

CHU de Quebec-Hopital l'Enfant-Jesus (HEJ), Quebec City, QC Canada

Anca Prica

Principal Investigator

University Health Network-Princess Margaret Hospital, Toronto, ON Canada

Eligibility Criteria

This trial is for individuals over 18 with newly diagnosed primary CNS lymphoma who can't have a stem cell transplant due to age or other health issues. They should be able to take high-dose methotrexate, ibrutinib, and rituximab, and not have had previous treatments except steroids. Participants need proper organ function and must be able to swallow pills without absorption problems.

Inclusion Criteria

I have a confirmed diagnosis of primary central nervous system lymphoma.

I am over 65 or have health issues that prevent me from undergoing high-dose chemotherapy and stem cell transplant, but can still receive specific treatments.

I have only used corticosteroids for my brain lymphoma and am on a low dose.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive methotrexate and ibrutinib, with rituximab if applicable, for 3 months, followed by ibrutinib alone for up to 2 years

Up to 2 years

Cycles 1-6, q14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits every 3 to 6 months depending on side effects

Approximately 6 years

Every 3-6 months

Treatment Details

Interventions

• Ibrutinib
• Methotrexate
• Rituximab

Trial Overview The study tests if adding Ibrutinib to the usual treatment (Rituximab and Methotrexate) is more effective in treating primary CNS lymphoma. It compares this new combination against the standard care most people receive for this type of cancer.

Participant Groups

Group I: Methotrexate, Ibrutinib +/- Rituximab Experimental Treatment 3 Interventions

Cycles 1-6, q14 days Day 1: Methotrexate + Rituximab Days 6-14: Ibrutinib daily orally

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?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

Janssen Inc.

Industry Sponsor

Trials

24

Recruited

8,100+

Findings from Research

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]

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 meta-analysis of 2456 CLL patients, ibrutinib was found to have a similar risk of anemia, thrombocytopenia, and neutropenia compared to control treatments, indicating a favorable safety profile for these adverse effects.

However, patients treated with ibrutinib experienced significantly higher rates of abdominal issues and diarrhea, suggesting that while it is effective, monitoring for gastrointestinal side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: A systematic review and meta-analysis of randomized trials. Zhou, Y., Lu, H., Yang, M., 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]

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]

Ibritumomab tiuxetan radioimmunotherapy demonstrated a 74% overall response rate in patients with rituximab-refractory follicular non-Hodgkin's lymphoma, indicating its efficacy as a treatment option for this difficult-to-treat population.

The treatment was well-tolerated with acceptable safety, as radiation doses to healthy organs were below safety limits, although it did lead to significant hematologic adverse events, including grade 4 neutropenia in 35% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. Witzig, TE., Flinn, IW., Gordon, LI., et al.[2022]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. 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]

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

Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: A systematic review and meta-analysis of randomized trials. [2022]

4. 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]

5. 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]

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

Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. [2022]

7. 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]