Ibrutinib + Rituximab + Lenalidomide for Central Nervous System Lymphoma

Recruiting at 8 trial locations

Overseen By Lauren Schaff, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anticoagulants, Immunosuppressants, CYP3A drugs

Disqualifiers: Active malignancy, Cardiovascular disease, HIV, 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: 12 months

25 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study drug. Specifically, you must stop using warfarin or similar blood thinners at least seven days before, and any drugs that affect the P450/CYP3A enzyme at least two weeks before. Additionally, you must stop any immunosuppressant therapy at least 28 days before the trial.

What data supports the effectiveness of the drug combination Ibrutinib, Rituximab, and Lenalidomide for Central Nervous System Lymphoma?

Research shows that the combination of Ibrutinib, Rituximab, and Lenalidomide has been effective in treating relapsed or refractory mantle cell lymphoma, and a case series suggests it may also be effective for relapsed/refractory primary CNS lymphoma. Additionally, Ibrutinib alone has shown promise in treating CNS lymphoma, indicating potential effectiveness when combined with other drugs. ^{1 2 3 4 5}

What makes the drug combination of Ibrutinib, Rituximab, and Lenalidomide unique for treating central nervous system lymphoma?

This drug combination is unique because it combines three powerful agents that target different aspects of the cancer cells, potentially improving effectiveness compared to using each drug alone. Ibrutinib is a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, making it particularly suitable for central nervous system involvement. ^{1 2 3 4 6}

What is the purpose of this trial?

The investigator's want to find out if treatment with ibrutinib, rituximab, and lenalidomide are safe and better than the usual approach in patients with recurrent or refractory central nervous system lymphoma.

Research Team

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with recurrent or refractory primary or secondary central nervous system lymphoma who have had at least one prior CNS therapy can join. They must be able to undergo MRI/CT scans, sign consent, and meet specific health criteria like adequate organ function and blood counts. Women of childbearing age need a negative pregnancy test and agree to birth control measures.

Inclusion Criteria

My cancer is confirmed as PCNSL or DLBCL through tissue examination.

I am able to get out of my bed or chair and move around.

My bone marrow and organs are functioning well.

Exclusion Criteria

I have had a stem cell transplant from a donor.

I am currently taking medication that affects liver enzyme CYP3A.

I am currently on medication that suppresses my immune system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ibrutinib, rituximab, and lenalidomide. Ibrutinib is given continuously, lenalidomide for 12 cycles, and rituximab for 6 cycles.

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Ibrutinib
• Lenalidomide
• Rituximab

Trial Overview The trial is testing the safety and effectiveness of combining three drugs: Ibrutinib, Rituximab, and Lenalidomide for patients with certain types of brain lymphomas that haven't responded well to previous treatments. The goal is to see if this combination works better than standard approaches.

Participant Groups

Group I: ibrutinib in combination with rituximab and lenalidomide Experimental Treatment 3 Interventions

Ibrutinib will be given day 1-28; Lenalidomide will be given day 1-21; Rituximab will be given on day 1. Rituximab is given for 6 cycles; Lenalidomide is given for 12 cycles; Ibrutinib is continued until disease progression, intolerable toxicity or death.

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 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]

The combination of rituximab, lenalidomide, and ibrutinib (R2I) showed a high response rate in 14 patients with relapsed/refractory primary CNS lymphoma, with 4 achieving complete response and 4 achieving partial response within a median of 2.5 months.

R2I was generally well-tolerated, with manageable toxicity leading to discontinuation in only 3 patients, and no deaths related to toxicity, indicating its potential as a treatment option for patients who have failed conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. Houillier, C., Chabrot, CM., Moles-Moreau, MP., et al.[2021]

A 77-year-old patient with primary central nervous system lymphoma (PCNSL) showed good tolerance and sustained remission after receiving ibrutinib as a consolidation therapy following high-dose methotrexate and rituximab plus temozolomide.

This case suggests that ibrutinib, a Bruton's tyrosine kinase inhibitor that can cross the blood-brain barrier, may be an effective option for elderly patients with PCNSL, but further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. Du, S., Bota, D., Kong, XT.[2022]

Ibrutinib, an oral Bruton tyrosine kinase inhibitor, demonstrated rapid and dramatic responses in 3 patients with symptomatic CNS relapse of mantle cell lymphoma, leading to almost immediate recovery from symptoms.

Pharmacokinetic analyses confirmed that ibrutinib effectively crosses the blood-brain barrier, with ongoing responses observed in patients from 2 months to 1 year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Bernard, S., Goldwirt, L., Amorim, S., et al.[2021]

A combination treatment of temozolomide, etoposide, doxorubicin, dexamethasone, rituximab, and the BTK inhibitor ibrutinib showed promising responses in patients with primary central nervous system lymphoma.

However, this treatment regimen was linked to significant toxicity, including serious infections like pulmonary and cerebral aspergillosis, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. Grommes, C., Younes, A.[2018]

References

1. 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]

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

Rituximab-Lenalidomide-Ibrutinib Combination for Relapsed/Refractory Primary CNS Lymphoma: A Case Series of the LOC Network. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Consolidation/Maintenance Therapy with Single Agent Ibrutinib for Primary CNS Lymphoma after Initial Induction Therapy. [2022]

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

Orelabrutinib versus ibrutinib for patients with refractory/relapsed primary central nervous system lymphoma: An efficacy and safety analysis. [2023]

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

Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. [2021]

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

Ibrutinib in PCNSL: The Curious Cases of Clinical Responses and Aspergillosis. [2018]