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)

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well acalabrutinib, lenalidomide, and rituximab work in treating patients with CD20 positive stage III-IV, grade 1-3a follicular lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib, lenalidomide, and rituximab may help to control the disease.

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.

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

Research shows that the combination of Lenalidomide and Rituximab is effective in treating follicular lymphoma, as it significantly prolongs the time patients live without the disease getting worse. This combination has shown promising results in patients with relapsed or refractory follicular lymphoma, making it an important treatment option. ^{1 2 3 4 5}

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

Lenalidomide and Rituximab, when used together, have a manageable safety profile in treating follicular lymphoma. Common side effects include neutropenia (low white blood cell count), which is usually managed with dose adjustments, and mild skin reactions. Serious side effects like venous thromboembolism (blood clots) are rare, and the treatment is generally well-tolerated. ^{1 3 4 6 7}

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

This drug combination is unique because it includes Acalabrutinib, a newer type of drug that targets specific proteins in cancer cells, combined with Lenalidomide and Rituximab, which have shown effectiveness in treating follicular lymphoma by modulating the immune system and targeting cancer cells. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment through different mechanisms of action. ^{1 2 3 4 5}

Research Team

Paolo Strati

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

References

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

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

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

Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. [2021]

3. 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]

4. 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]

5. England 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. [2020]

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

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. [2020]

7. United States 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. [2021]