Ibrutinib + Rituximab + Lenalidomide for Central Nervous System Lymphoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—ibrutinib (a Bruton's tyrosine kinase inhibitor), rituximab, and lenalidomide—to determine their safety and effectiveness compared to standard treatments for recurrent or hard-to-treat central nervous system lymphoma. The trial targets patients who have received prior treatment but still have active disease. Individuals diagnosed with primary central nervous system lymphoma or diffuse large B-cell lymphoma that has returned or resisted treatment may be suitable candidates. The trial seeks to find better management options for these challenging cancer types. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking cancer research.

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.

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

Research has shown that the combination of ibrutinib, rituximab, and lenalidomide has been promising. One study examined patients with various types of lymphoma and found that this combination was generally well-tolerated. While some patients experienced side effects, most were mild to moderate, including low blood cell counts, tiredness, and nausea.

Another study focused on central nervous system lymphoma, similar to the condition in this trial. It demonstrated that the treatment positively affected the disease, with manageable side effects. Most patients handled the treatment well, though some experienced more serious side effects like infections.

Overall, existing research suggests that while side effects occur, they are often manageable, and the treatment has been effective in many cases. However, as this is an early-phase trial, the primary focus is on safety. All potential participants should discuss risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for central nervous system lymphoma, which often include chemotherapy and radiation, this combination of ibrutinib, rituximab, and lenalidomide targets the cancer in a unique way. Ibrutinib is a Bruton's tyrosine kinase inhibitor, which disrupts essential pathways for cancer cell survival. Lenalidomide modulates the immune system to help fight the cancer, and rituximab is a monoclonal antibody that specifically targets and helps destroy cancerous cells. Researchers are excited about this treatment because it combines these powerful mechanisms, potentially offering a more effective and targeted approach than existing options.

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

This trial will evaluate the effectiveness of a combination of three drugs—ibrutinib, rituximab, and lenalidomide—in treating central nervous system lymphoma. Research has shown that this combination may be effective, with studies finding that about one-third of patients experienced positive results lasting over a year. Specifically, ibrutinib has improved patient responses to treatment for these types of lymphoma. This combination blocks signals that help cancer cells grow, making survival more difficult for them. Early results suggest this treatment could be a strong option for individuals with recurring or difficult-to-treat central nervous system lymphoma. ^{2 3 4 6 7}

Who Is on the Research Team?

Christian Grommes, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

Patient has a life-threatening illness, medical condition, or organ system dysfunction that could compromise the subject's safety

I am currently taking medication that affects liver enzyme CYP3A.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40269592/

Phase Ib study with expansion of ibrutinib, lenalidomide, and ... Median PFS was limited but 1/3 of patients had durable responses >12 months. This trial was registered at www.clinicaltrials.gov (NCT03703167).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02077166

Study Details | NCT02077166 | Ibrutinib in Combination ... This Phase 1b/2 study is designed to assess the safety and efficacy of ibrutinib in combination with lenalidomide and rituximab in subjects with relapsed/ ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824003408

Efficacy and safety of ibrutinib in central nervous system ... Our analysis investigated the effect of Ibrutinib on the overall response rate in patients with central nervous system lymphoma, using data from 13 studies. The ...

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6275/500565/Rituximab-Ibrutinib-Lenalidomide-R2I-Combination

Rituximab Ibrutinib Lenalidomide (R2I) Combination for ... Background: Primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) each carry a poor prognosis.

5. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03703167/

Clinical Trial: NCT03703167 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10922670/

Safety and Efficacy of Ibrutinib in Combination with Rituximab ... Here we report the results of a frontline, open-label, phase II clinical trial of ibrutinib, lenalidomide and rituximab for previously untreated patients with ...

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

Ibrutinib combined with rituximab and high-dose methotrexate ... In this pilot study, the IRM regimen (ibrutinib, rituximab, and HD-MTX) demonstrated promising outcomes in newly diagnosed primary diffuse large ...