Combination Therapy for Lymphoma

Recruiting at 8 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding a new drug, ibrutinib, to the usual treatment can better prevent the growth or spread of primary central nervous system lymphoma (PCNSL), a type of brain cancer. Participants will receive a combination of drugs: methotrexate, ibrutinib, and sometimes rituximab. The trial seeks individuals with PCNSL who have not received other systemic treatments for it besides steroids and cannot undergo high-dose chemotherapy. Those meeting these criteria might be a good fit. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

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.

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

Research has shown that using ibrutinib, methotrexate, and rituximab together is generally safe and well-tolerated. In earlier studies, patients with primary central nervous system lymphoma (PCNSL) who took these drugs experienced promising outcomes. The treatment proved effective and maintained a good safety record.

One study found that patients managed this combination well as a first treatment option. Another study, which focused on patients with recurring or difficult-to-treat PCNSL, reported similar positive results.

Overall, these studies suggest that the treatment is safe, with most patients handling it well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for lymphoma, which often involve chemotherapy or radiation, the combination of Ibrutinib, Methotrexate, and Rituximab targets the disease in a unique way. Ibrutinib works differently by inhibiting a specific protein called Bruton's tyrosine kinase, which plays a crucial role in the growth and survival of cancer cells. Methotrexate and Rituximab are already known for their effectiveness, but when combined with Ibrutinib, there’s potential for enhanced results by disrupting cancer cell communication and survival pathways more effectively. Researchers are excited because this combination could offer a more targeted approach, potentially leading to better outcomes with fewer side effects compared to traditional therapies.

What evidence suggests that this trial's treatments could be effective for primary central nervous system lymphoma?

This trial will evaluate the combination of methotrexate, ibrutinib, and rituximab for treating primary central nervous system lymphoma (PCNSL). Studies have shown promising results for this combination. After the initial treatment, all patients responded positively: 77.8% had a complete response, with their cancer undetectable, and 22.2% had a partial response, with their cancer reduced but not gone. Another study found that 75.7% of patients achieved a complete response. This combination has improved patient response and survival rates for newly diagnosed PCNSL, with no serious side effects reported. These results suggest that adding ibrutinib to the usual treatment might control the cancer more effectively. ^{1 2 3 5 6}

Who Is on the 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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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 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 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]

Citations

1. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1579483/full

Clinical outcomes of newly diagnosed PCNSL treated with ... Conclusions: RMA in combination with ibrutinib regimen improved response rates and survival in newly diagnosed PCNSL with no serious adverse ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12527878/

Ibrutinib combined with rituximab and high-dose methotrexate ... After induction, overall response rate (ORR) was 100% (complete response [CR]: 77.8%, partial response [PR]: 22.2%). Post-consolidation, CR ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41114362/

a pilot study with long-term follow-up Results: After induction, overall response rate (ORR) was 100% (complete response [CR]: 77.8%, partial response [PR]: 22.2%). Post-consolidation ...

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6539/526350/Ibrutinib-Rituximab-and-High-Dose-Methotrexate-in

Ibrutinib, Rituximab, and High-Dose Methotrexate in Newly ... Current Status: As of June 30, 2024, the median follow-up was 25.1 months. Of the 32 enrolled patients, 8 patients were withdrawn due to drug ...

5. nature.com nature.com/articles/s41408-025-01278-w

Prospective phase II trial of first-line rituximab ... Within this cohort, 28 patients achieved CRs (75.7%) and 8 patients achieved PRs (21.6%). Upon completion of induction therapy, 31 out of 37 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04514393

Ibrutinib With Methotrexate and Temozolomide for Patients ... Grommes et al.have shown ibrutinib in combination with methotrexate and rituximab are safe and shows promising activity in recurrent/refractory CNS lymphoma.