Rituximab + Lenalidomide + Ibrutinib for Follicular Lymphoma

Not currently recruiting at 7 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three drugs—lenalidomide, ibrutinib, and rituximab—to treat follicular lymphoma, a type of blood cancer. Researchers aim to find the best dose and identify any side effects when these drugs are used together. Lenalidomide and ibrutinib work to stop cancer cells from growing, while rituximab helps the immune system attack the cancer. Individuals diagnosed with stage II-IV follicular lymphoma who have not yet received treatment may be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

Research has shown that the combination of ibrutinib, lenalidomide, and rituximab has been tested for safety in patients with follicular lymphoma. One study found that while this combination can be effective, it often causes skin rashes, affecting about 82% of patients to varying degrees. More severe side effects occurred more frequently compared to past data with just lenalidomide and rituximab. Despite these side effects, the treatments are generally manageable. Each drug has a specific role: lenalidomide boosts the immune system, ibrutinib stops cancer cells from growing, and rituximab helps the immune system destroy cancer cells. Understanding these potential side effects and benefits can assist in deciding about joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of rituximab, lenalidomide, and ibrutinib for follicular lymphoma because it brings together three powerful mechanisms of action. Rituximab targets and destroys specific cancer cells by binding to the CD20 protein. Lenalidomide enhances the immune system's ability to fight cancer and can inhibit tumor growth. Ibrutinib blocks a key protein that helps cancer cells survive and spread. This combination could potentially offer a more comprehensive attack on the cancer than current standard treatments, which often involve chemotherapy and rituximab alone.

What evidence suggests that this treatment might be an effective treatment for follicular lymphoma?

Research has shown that the combination of ibrutinib, lenalidomide, and rituximab, which participants in this trial will receive, may effectively treat follicular lymphoma, a type of blood cancer. Studies have found that this combination works well as an initial treatment for patients who have not yet tried other therapies. It has demonstrated similar results in delaying disease progression compared to other treatments, with some patients experiencing longer periods without their cancer worsening. Rituximab helps the immune system identify and destroy cancer cells. Lenalidomide strengthens the immune system, while ibrutinib inhibits essential enzymes that cancer cells need to grow. Together, these drugs may help prevent the cancer from growing and spreading. ^{1 3 6 7 8}

Who Is on the Research Team?

Chaitra S Ujjani

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37985359/

Safety and efficacy of ibrutinib in combination with rituximab ... IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 ...

2. 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 ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01829568

Rituximab, Lenalidomide, and Ibrutinib in Treating Patients ... This may help the immune system kill cancer cells. Giving lenalidomide and ibrutinib together with rituximab may work well in treating follicular lymphoma.

4. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6260/505326/Real-World-Efficacy-and-Safety-of-Rituximab

Real-World Efficacy and Safety of Rituximab, Lenalidomide ... Our results suggest that RLI is a viable therapeutic option with promising activity and favorable toxicity profile in patients with R/R NHL patients.

5. nature.com nature.com/articles/s41467-025-62509-z

Frontline acalabrutinib, lenalidomide and rituximab for ... This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with ...

6. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35114

Safety and efficacy of ibrutinib in combination with rituximab ... Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3–4 toxicity, particularly rash. The study was ...

7. ashpublications.org ashpublications.org/blood/article/128/21/2510/35716/Phase-1-trial-of-rituximab-lenalidomide-and

Phase 1 trial of rituximab, lenalidomide, and ibrutinib in ... Key Points. The combination of rituximab, lenalidomide, and ibrutinib is associated with a high incidence of rash in follicular lymphoma (all grades 82%).E.

8. mdanderson.elsevierpure.com mdanderson.elsevierpure.com/en/publications/safety-and-efficacy-of-ibrutinib-in-combination-with-rituximab-an

Safety and efficacy of ibrutinib in combination with ... Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: ...