Ibrutinib + Lenalidomide + Rituximab for Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Hackensack Meridian Health

Must be taking: Aspirin

Must not be taking: Warfarin

Disqualifiers: CNS involvement, HIV, Hepatitis, 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: 30

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three drugs (ibrutinib, lenalidomide, and rituximab) in patients with mantle cell lymphoma who have not responded to other treatments. Ibrutinib stops cancer cell growth, lenalidomide boosts the immune system, and rituximab helps the immune system target cancer cells. Lenalidomide and rituximab have shown significant activity in mantle cell lymphoma, both as monotherapies and in combination. The goal is to find the best dose and see how well this combination works.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot use warfarin or other Vitamin K antagonists. Also, you must not have used any standard chemotherapy, radiation therapy, or experimental drug therapy for MCL within 21 days before starting the trial.

What data supports the effectiveness of the drug combination Ibrutinib, Lenalidomide, and Rituximab for treating lymphoma?

Research shows that the combination of Ibrutinib, Lenalidomide, and Rituximab is effective for patients with relapsed or refractory mantle cell lymphoma, with a high overall response rate of 88% and a complete response rate of 83%. This combination has also been found to be safe and tolerable, even in patients with high-risk features. ^{1 2 3 4 5}

Is the combination of Ibrutinib, Lenalidomide, and Rituximab safe for humans?

The combination of Ibrutinib, Lenalidomide, and Rituximab has been studied in patients with certain types of lymphoma, and it appears to be generally safe. Some common side effects include rash, low white blood cell counts, and low platelet counts, but these were manageable in the studies. ^{1 3 4 5 6}

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

This drug combination is unique because it combines three different mechanisms: Ibrutinib inhibits a protein important for B-cell activity, Lenalidomide modulates the immune system, and Rituximab targets and helps clear B-cells. This combination aims to improve effectiveness compared to using these drugs separately, especially in relapsed or hard-to-treat lymphomas. ^{1 3 7 8 9}

Research Team

Andre Goy, MD

Principal Investigator

Hackensack Meridian Health

Eligibility Criteria

This trial is for adults over 18 with Mantle Cell Lymphoma that has come back or hasn't responded to treatment. They must have had at least one prior therapy, be in decent physical shape (ECOG ≤2), and have certain blood counts within normal ranges. Women who can have children need a negative pregnancy test and must follow specific safety programs.

Inclusion Criteria

My diagnosis of mantle cell lymphoma (MCL) is confirmed by lab tests.

I have at least one measurable tumor or lymph node.

My kidney function is normal, with a creatinine level below 2.

Exclusion Criteria

Other medical conditions that would potentially interfere with patient participation in this trial

I am currently taking warfarin or similar blood thinners.

I do not have a serious infection or it has been treated.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Treatment

Participants receive ibrutinib, lenalidomide, and rituximab to determine the maximum tolerated dose (MTD) and/or recommended phase II dose

6 cycles

Response is evaluated after 2, 4, and 6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Through 28 days after discontinuation of study drug

Treatment Details

Interventions

• Ibrutinib
• Lenalidomide
• Rituximab

Trial Overview The study aims to find the safest dose of Ibrutinib combined with Lenalidomide/Rituximab for patients with relapsed/refractory Mantle Cell Lymphoma. It's a step-by-step process where doses are increased to determine the maximum tolerated dose or recommended phase II dose.

Participant Groups

Group I: Dose Escalation Study Experimental Treatment 3 Interventions

Ibrutinib 560 mg/daily rituximab 375mg/m2 IV Day 1 Lenalidomide 10-25 mg PO days 1-21

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?

Hackensack Meridian Health

Lead Sponsor

Trials

141

Recruited

42,900+

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]

Ibrutinib, a Bruton's kinase inhibitor, has shown a high overall response rate of 68% in patients with relapsed or refractory mantle cell lymphoma, with a median progression-free survival of 13.9 months, indicating its efficacy as a treatment option.

In a phase 3 trial for chronic lymphocytic leukemia, ibrutinib demonstrated a significantly higher response rate (43% vs. 4% for ofatumumab) and improved overall survival (90% vs. 81% at 12 months), while being well tolerated with no dose-limiting toxicity, making it a suitable option for older patients and those not eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib. Lee, CS., Rattu, MA., Kim, SS.[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 the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

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

Phase 1b dose-finding study of rituximab, lenalidomide, and ibrutinib (R2I) in patients with relapsed/refractory mantle cell lymphoma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

The iR2 regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: A multicentre, non-randomised, open-label phase 2 study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma: Phase I trial results. [2022]

7. 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]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. [2021]

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

Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma. [2023]