Rituximab + Lenalidomide + Ibrutinib for Follicular Lymphoma

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inhibitors, Warfarin

Disqualifiers: CNS involvement, Cardiovascular disease, 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: 5

Duration: 18 cycles of 28 days each

33 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had chemotherapy, radiotherapy, or major surgery for non-lymphoma conditions within 4 weeks before joining. Also, you cannot use strong inhibitors or inducers of certain liver enzymes (CYP3A4/5) or be on warfarin.

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

The combination of Rituximab, Lenalidomide, and Ibrutinib has been studied in various conditions, showing some safety concerns. Common side effects include fatigue, diarrhea, nausea, and rash, with more serious issues like neutropenia (low white blood cell count) and other blood-related problems occurring less frequently. These findings suggest that while the treatment can be effective, it may also require careful monitoring for side effects. ^{1 2 3 4 5}

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

This drug combination is unique because it combines three active agents, each with different mechanisms, to potentially improve treatment efficacy for follicular lymphoma. Ibrutinib targets a specific enzyme involved in cancer cell growth, while Lenalidomide modulates the immune system, and Rituximab targets cancer cells directly, offering a comprehensive approach compared to using these drugs individually. ^{1 2 6 7 8}

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of lenalidomide and ibrutinib when given together with rituximab in treating patients with previously untreated stage II-IV follicular lymphoma. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving lenalidomide and ibrutinib together with rituximab may work well in treating follicular lymphoma.

Research Team

Chaitra S Ujjani

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for adults with previously untreated stage II-IV follicular lymphoma. Eligible participants must have a certain level of health, including no severe heart conditions, uncontrolled seizures, or active infections like HIV above specific thresholds. They should not be pregnant or nursing and must agree to use effective birth control methods.

Inclusion Criteria

- No evidence of coinfection with hepatitis B or C

- CD4+ cell count >= 400/mm^3

- Patients must not be receiving concurrent treatment with other investigational drugs

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive lenalidomide orally once daily on days 1-21 and ibrutinib orally once daily on days 1-28. Treatment repeats every 28 days for up to 18 cycles. Rituximab is administered intravenously on days 1, 8, 15, and 22 of cycle 1 and once weekly at weeks 13, 21, 29, and 37.

18 cycles of 28 days each

Weekly visits during cycle 1, then at weeks 13, 21, 29, and 37

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 4 months for 2 years, then every 6 months for 8 years.

10 years

Every 4 months for 2 years, then every 6 months

Treatment Details

Interventions

• Ibrutinib
• Lenalidomide
• Rituximab

Trial Overview The study tests the combination of lenalidomide and ibrutinib with rituximab to treat follicular lymphoma. Lenalidomide may help the immune system halt cancer growth; ibrutinib blocks enzymes needed by cancer cells; rituximab targets CD20 on B cells and some cancers.

Participant Groups

Group I: Treatment (lenalidomide, ibrutinib, and rituximab) Experimental Treatment 3 Interventions

Patients receive lenalidomide PO QD on days 1-21 and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV on days 1, 8, 15, and 22 of cycle 1 and once weekly at weeks 13, 21, 29, and 37.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

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]

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 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]

The combination of lenalidomide and rituximab (LR) showed a significantly higher overall response rate (76%) compared to lenalidomide alone (53%) in patients with recurrent follicular lymphoma, indicating that LR is more effective in treating this condition.

Both treatment regimens had similar rates of severe adverse events (grade 3 to 4), but lenalidomide alone resulted in more treatment failures, suggesting that LR may provide a better balance of efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). Leonard, JP., Jung, SH., Johnson, J., et al.[2022]

In a phase II trial involving 66 patients with untreated follicular lymphoma, the combination of lenalidomide and rituximab achieved a high overall response rate of 95% and a complete response rate of 72%, indicating strong efficacy.

The treatment was associated with low rates of severe toxicity (grade 3-4), with a 5-year overall survival rate of 100%, suggesting that lenalidomide plus rituximab could be a safe and effective alternative to traditional chemotherapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Martin, P., Jung, SH., Pitcher, B., et al.[2023]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103. [2021]

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

A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL. [2021]

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

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

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

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). [2022]

8. England pubmed.ncbi.nlm.nih.gov

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). [2023]