Acalabrutinib + Lenalidomide + Rituximab for Follicular Lymphoma

Overseen By Paolo Strati

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Anticoagulants, CYP3A inhibitors, CYP3A inducers, PPIs

Disqualifiers: CNS lymphoma, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 13 cycles (approximately 12 months)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—acalabrutinib, lenalidomide, and rituximab—to evaluate their effectiveness in treating follicular lymphoma, a type of blood cancer. Acalabrutinib, a targeted therapy, may block enzymes necessary for cancer cell growth. Lenalidomide helps prevent tumor cells from growing or spreading, while rituximab, an antibody therapy, targets and inhibits cancer cell growth. Individuals with CD20 positive follicular lymphoma in stages III or IV who have not received previous treatment might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take certain drugs like strong CYP3A inhibitors or inducers, warfarin, or proton pump inhibitors. If you're on these, you may need to stop them before starting the trial.

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

Research shows that the combination of acalabrutinib, lenalidomide, and rituximab is generally well-tolerated by patients with follicular lymphoma. Studies have found this treatment safe and effective for first-time users. Some patients have experienced mild side effects, but the overall safety remains manageable. Although minor reactions may occur, the combination is considered safe enough for clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combining acalabrutinib, lenalidomide, and rituximab for follicular lymphoma because it offers a unique approach compared to standard therapies like chemotherapy and monoclonal antibodies alone. Acalabrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, targets the B-cell receptor signaling pathway, which is crucial for the survival of cancerous B-cells in follicular lymphoma. This mechanism is different from most existing treatments, which often focus on depleting B-cells or inhibiting their growth. By combining this with lenalidomide’s immune-modulating effects and rituximab’s ability to target and mark cancer cells for destruction, this treatment aims to offer a more comprehensive assault on the cancer, potentially improving outcomes and minimizing disease progression.

What evidence suggests that acalabrutinib, lenalidomide, and rituximab might be effective for follicular lymphoma?

Research has shown that the combination of acalabrutinib, lenalidomide, and rituximab, which participants in this trial will receive, may effectively treat follicular lymphoma. Studies have found this combination to be both active and safe for patients who have not yet received treatment for this type of cancer. Acalabrutinib blocks certain enzymes that cancer cells need to grow. Lenalidomide either kills cancer cells or stops them from multiplying. Rituximab specifically targets cancer cells, helping to stop their growth and spread. Together, these drugs have shown promise in managing the disease. ^{1 2 3 4 5}

Who Is on the Research Team?

Paolo Strati

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with CD20 positive stage III-IV, grade 1-3a follicular lymphoma who haven't had prior systemic treatment. They must have measurable disease, meet certain criteria for starting treatment, and be in good physical condition with adequate organ function. Participants need to use effective birth control and cannot be pregnant or breastfeeding.

Inclusion Criteria

I have a tumor that is at least 2 cm large, confirmed by imaging tests.

I have not received any treatment for lymphoma before.

Specific blood count requirements: ANC >= 1,000/mm^3, Platelet counts >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement with lymphoma, Hemoglobin > 8 g/dL

Exclusion Criteria

I do not have any major heart conditions.

I am not pregnant, breastfeeding, or taking experimental drugs.

I have not taken certain medications that are not allowed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib, lenalidomide, and rituximab. Acalabrutinib is taken orally twice daily on days 1-28. Starting from cycle 2, lenalidomide is taken orally once daily on days 1-21, and rituximab is administered intravenously on days 1, 8, 15, and 22 of cycle 2 and day 1 of subsequent cycles. Treatment repeats every 28 days for 13 cycles.

13 cycles (approximately 12 months)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 1 year and then every 6 months for 2 years.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Lenalidomide
• Rituximab

Trial Overview The study tests a combination of acalabrutinib (blocks enzymes needed for cancer cell growth), lenalidomide (chemotherapy that kills or stops tumor cells from dividing), and rituximab (monoclonal antibody against cancer cells). It aims to see how well these drugs work together in controlling this type of lymphoma.

How Is the Trial Designed?

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

Patients receive acalabrutinib PO BID on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21 and rituximab IV on days 1, 8, 15, and 22 of cycle 2 and day 1 of subsequent cycles. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity.

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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 study involving 1030 patients with previously untreated follicular lymphoma, the combination of rituximab and lenalidomide showed similar efficacy to rituximab plus chemotherapy, with complete response rates of 48% and 53% respectively at 120 weeks.

The safety profiles differed between the two treatments, with rituximab-chemotherapy leading to higher rates of severe neutropenia, while rituximab-lenalidomide was associated with more severe skin reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. Morschhauser, F., Fowler, NH., Feugier, P., et al.[2021]

In a phase II trial involving 45 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), transformed large cell lymphoma (TL), or grade 3 follicular lymphoma, the combination of lenalidomide and rituximab showed an overall response rate of 33% and a median response duration of 10.2 months.

The treatment was well tolerated, with significant hematological toxicities observed, and patients who underwent stem cell transplantation after responding to the therapy experienced a prolonged response duration of 30.9 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Wang, M., Fowler, N., Wagner-Bartak, N., et al.[2020]

The combination of rituximab and lenalidomide (R2) significantly improves treatment efficacy for recurrent non-Hodgkin lymphoma compared to rituximab alone, leading to its approval for use in previously treated patients with follicular and marginal zone lymphoma.

R2 has a manageable safety profile, with common adverse events including grade 3/4 neutropenia, skin rashes, and gastrointestinal issues, indicating that while it is effective, careful monitoring and management of side effects are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma. Cheson, BD., Morschhauser, F., Martin, P.[2021]

Lenalidomide, especially when combined with rituximab (the 'R(2)' regimen), shows enhanced efficacy in treating indolent B-cell and mantle cell lymphomas, even in patients resistant to rituximab, while maintaining a manageable safety profile.

The most common serious side effect is asymptomatic neutropenia, which can be managed through dose adjustments, and while immune-related symptoms like rash are more frequent with the R(2) regimen, they are generally low-grade and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. Ruan, J., Shah, B., Martin, P., et al.[2020]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40775236/

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 advanced ...

2. 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 ...

3. onclive.com onclive.com/view/acalabrutinib-plus-lenalidomide-and-rituximab-is-safe-and-active-in-untreated-follicular-lymphoma

Acalabrutinib Plus Lenalidomide and Rituximab Is Safe ... Acalabrutinib plus lenalidomide and rituximab displayed activity and had a tolerable safety profile in first-line follicular lymphoma.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04404088

NCT04404088 | Acalabrutinib, Lenalidomide, and ... This phase II trial studies how well acalabrutinib, lenalidomide, and rituximab work in treating patients with CD20 positive stage III-IV, ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11886943/

Acalabrutinib in combination with rituximab and lenalidomide ... This phase 1b open‐label, dose‐finding study evaluated acalabrutinib in combination with rituximab plus lenalidomide 15 or 20 mg in 29 patients with relapsed ...