Rituximab + Pembrolizumab +/- Lenalidomide for Lymphoma

Overseen By Clinical Research Operations UT MD Anderson Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Rituximab, CAR T cell

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Active CNS lymphoma, 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

Compensation: Varies

Number of Visits: 3

Duration: 1-2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of a drug combination, including rituximab and pembrolizumab, with or without lenalidomide (Revlimid), against certain types of lymphoma, specifically follicular lymphoma and diffuse large B-cell lymphoma. These drugs assist the immune system in targeting cancer cells and may prevent the cancer from growing and spreading. The trial suits individuals whose lymphoma has returned after treatments like rituximab or CAR T cell therapy and who experienced a partial or complete response to rituximab lasting at least six months. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on systemic steroid therapy or other immunosuppressive treatments within 7 days before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that combining rituximab and pembrolizumab is generally safe for patients with relapsed or refractory follicular lymphoma, with most side effects being mild, such as tiredness or fever. Adding lenalidomide maintains similar safety levels. Early results suggest this combination is effective against certain types of lymphoma. However, some patients may experience more serious side effects, like changes in blood cell counts or infections, though these are uncommon.

In summary, while the treatment is mostly well-tolerated, some individuals may experience mild to moderate side effects. It is important to discuss potential risks and benefits with a healthcare provider before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lymphoma because they combine powerful drugs with unique mechanisms of action. Rituximab, a monoclonal antibody, targets the CD20 protein on B-cells, which is a common approach. However, pembrolizumab, an immune checkpoint inhibitor, unleashes the body's immune system by targeting the PD-1 pathway, a relatively new strategy in lymphoma treatment. Adding lenalidomide, which modifies the immune response and has anti-cancer effects, potentially enhances this combination. Together, these treatments aim to improve outcomes by using a multi-pronged attack on lymphoma cells, offering hope for better effectiveness than current standard therapies.

What evidence suggests that this trial's treatments could be effective for lymphoma?

Research shows that using rituximab and pembrolizumab together effectively treats relapsed follicular lymphoma. Studies have found that about 50% of patients with this type of lymphoma experience a complete response to this combination. In this trial, some participants will receive rituximab and pembrolizumab, while others will receive these two drugs along with lenalidomide. Adding lenalidomide has shown promise in treating various lymphomas, with high response rates in some cases. These three drugs together may help the immune system better attack cancer cells. Overall, these treatments have produced positive results in previous patients, making them a strong option for managing these lymphomas. ^{1 3 4 5 6}

Who Is on the Research Team?

Ranjit Nair

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with relapsed follicular lymphoma or diffuse large B-cell lymphoma after at least one prior therapy including rituximab, or two therapies with CAR T cell treatment. Participants must have adequate organ function, not be pregnant or breastfeeding, agree to use contraception, and cannot have certain infections like HIV or hepatitis.

Inclusion Criteria

Creatinine clearance will be calculated per institutional standard

Either the subject or his/her legally authorized representative be willing and able to provide written informed consent for the trial

Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

Exclusion Criteria

I have fully recovered from any major surgery before starting treatment.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I have been treated with specific immune system targeting drugs before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive rituximab and pembrolizumab, with or without lenalidomide, depending on the cohort. Treatment cycles last up to 1 year for Cohort I and up to 2 years for Cohort II.

1-2 years

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days, every 3 months for 1 year, and then every 6 months thereafter.

Up to 2 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Pembrolizumab
• Rituximab

Trial Overview The study tests the effectiveness of combining rituximab and pembrolizumab with or without lenalidomide in treating patients whose lymphoma has returned. It examines how these drugs might help the immune system fight cancer and stop tumor growth.

How Is the Trial Designed?

Group I: Cohort II (rituximab, pembrolizumab, lenalidomide) Experimental Treatment 4 Interventions

Patients receive rituximab IV over 4-8 hours on days 1, 8 and 15 of cycle 1, and day 1 of cycle 2. Patients also receive pembrolizumab IV over 1 hour on day 2 every 3 weeks for up to 2 years, and lenalidomide PO on days 1-14 every 3 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Cohort I (rituximab, pembrolizumab) Experimental Treatment 3 Interventions

Patients receive rituximab IV over 4-8 hours on days 1, 8, 15, and 22. Patients also receive pembrolizumab IV over 1 hour on day 2 every 3 weeks for up to 16 cycles (1 year) in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone 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 phase 2 trial involving 27 patients with rituximab-resistant B-cell lymphomas, the combination of lenalidomide, low-dose dexamethasone, and rituximab resulted in a significant increase in overall response rates from 29% after initial treatment to 58% after adding rituximab.

The median progression-free survival for patients was 23.7 months, indicating that this combination therapy not only enhances response rates but also provides durable benefits for patients with difficult-to-treat lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Ahmadi, T., Chong, EA., Gordon, A., et al.[2018]

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]

Lenalidomide, when used in combination with rituximab, has been shown to be an effective treatment for patients with relapsed or refractory follicular lymphoma, offering a chemotherapy-free option.

This combination therapy improves outcomes compared to using rituximab alone and may serve as a viable alternative to traditional chemoimmunotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in follicular lymphoma. Flowers, CR., Leonard, JP., Fowler, NH.[2021]

In a phase II trial involving 50 patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab, the combination of lenalidomide and rituximab resulted in a significant increase in overall response rate from 30.2% after lenalidomide alone to 62.8% after adding rituximab.

The median progression-free survival for patients receiving the lenalidomide-rituximab combination was 22.2 months, which was significantly longer than the 9.13 months observed with prior rituximab treatment, indicating that this combination can effectively overcome previous resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Chong, EA., Ahmadi, T., Aqui, NA., et al.[2022]

Lenalidomide is an effective and well-tolerated treatment for multiple myeloma and shows promise for patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma.

The review highlights the potential of lenalidomide, especially in combination with rituximab, as a therapeutic option, aiming to guide future clinical studies to enhance survival rates for these lymphoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. Desai, M., Newberry, KJ., Romaguera, J., et al.[2021]

In a phase II study involving 59 adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the combination of lenalidomide and rituximab resulted in a 66% overall response rate, indicating significant efficacy as a salvage therapy.

While the treatment showed promise, it was associated with notable side effects, particularly neutropenia in 73% of patients, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. Badoux, XC., Keating, MJ., Wen, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8864656/

Safety and activity of pembrolizumab in combination with ... In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL.

2. lymphomahub.com lymphomahub.com/medical-information/efficacy-and-safety-of-rituximab-and-pembrolizumab-in-rr-wm-pembrowm-trial

Efficacy and safety of rituximab and pembrolizumab in R/ ... Kothari et al. published results from the phase II PembroWM trial evaluating the efficacy and safety of pembrolizumab and rituximab ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.7519

Interim results of an on open-label, phase II study. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open- ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S000649712312742X

Pembrolizumab with Rituximab in Relapsed/Refractory ... Pembrolizumab + rituximab (PR) produced a complete response (CR) in 50% of patients with rituximab-sensitive, relapsed/refractory (R/R) FL.

5. onclive.com onclive.com/view/dr-nastoupil-on-efficacy-with-pembrolizumab-and-rituximab-in-follicular-lymphoma

Dr. Nastoupil on Efficacy With Pembrolizumab ... - OncLive The combination strategy could be synergistic in enhancing the patients' immune systems to target their follicular lymphoma cells. This phase II ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02446457

NCT02446457 | Rituximab and Pembrolizumab With or ... This phase II trial studies how well rituximab and pembrolizumab with or without lenalidomide works in treating patients with follicular lymphoma and ...