Lenalidomide + Nivolumab for Lymphoma

Recruiting at 49 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Sulfonamides, NSAIDs, others

Disqualifiers: Autoimmune disorders, HIV, others

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

Compensation: Varies

Number of Visits: 22

47 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of drugs to treat a rare brain cancer. The treatment aims to starve the tumor, boost the immune system, and stop cancer cells from growing. It targets patients with primary CNS lymphoma who may not respond well to standard treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that certain drugs like sulfonamide drugs, trimethoprim, and others should be stopped at least 48 hours before methotrexate administration. It's best to discuss your specific medications with the trial team.

What evidence supports the effectiveness of the drugs Lenalidomide and Nivolumab for treating lymphoma?

Rituximab, a drug often used in combination with other treatments for lymphoma, has shown significant improvements in outcomes for patients with non-Hodgkin's lymphoma, including better survival rates and response rates. This suggests that combining targeted therapies like Rituximab with other drugs could be effective in treating lymphoma. ^{1 2 3 4 5}

What is the safety profile of rituximab in humans?

Rituximab is generally well tolerated, but it can cause some side effects like high blood pressure, swelling, and rare heart issues. It may also increase the risk of infections, including serious ones like hepatitis B reactivation and a rare brain infection called PML. ^{6 7 8 9 10}

What makes the drug Lenalidomide + Nivolumab unique for treating lymphoma?

The combination of Lenalidomide and Nivolumab for lymphoma is unique because Lenalidomide is an oral immunomodulatory drug that enhances the immune system's ability to fight cancer cells, and when combined with Nivolumab, an immune checkpoint inhibitor, it may offer a novel approach to overcoming resistance to traditional treatments like Rituximab, especially in patients with certain types of B-cell lymphomas. ^{11 12 13 14 15}

Research Team

Alvaro J Alencar

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

Adults diagnosed with primary CNS diffuse large B-cell lymphoma who haven't had prior chemotherapy, radiation, or organ/stem cell transplants. They must have a certain level of physical function and adequate blood counts. Pregnant or nursing women are excluded, as well as those with autoimmune diseases that could affect the trial's safety.

Inclusion Criteria

I have not had chemotherapy or radiation for lymphoma.

Absolute neutrophil count (ANC) >= 1,500/mm^3

I can perform daily activities with some assistance.

Exclusion Criteria

You haven't had a serious allergic reaction to any type of antibody medication before.

I have stopped taking certain medications like pain relievers and antibiotics 48 hours before methotrexate treatment.

I do not have untreated HIV or a low CD4+T-cell count.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Patients receive rituximab, methotrexate, lenalidomide, and nivolumab. Treatment repeats every 14 days for up to 6 cycles.

12 weeks

6 visits (in-person)

Maintenance

Patients receive lenalidomide and nivolumab. Treatment repeats every 28 days for up to 12 cycles.

48 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 4 years

Every 3 months for 2 years, then every 6 months for up to 2 years

Treatment Details

Interventions

• Lenalidomide
• Methotrexate
• Nivolumab
• Rituximab

Trial Overview The trial is testing if adding Lenalidomide to Nivolumab along with usual drugs Rituximab and Methotrexate can improve treatment for primary CNS lymphoma. It aims to find the best dose and see if these drugs can extend control over the cancer after initial success.

Participant Groups

Group I: Treatment (rituximab, methotrexate, lenalidomide, nivolumab) Experimental Treatment 11 Interventions

INDUCTION: Patients receive rituximab IV on day 1, methotrexate IV over 2 hours or PO on day 2, lenalidomide PO daily on days 5-9, and nivolumab IV over 30 minutes on day 14. (In dose level IV that includes nivolumab, the doses of rituximab for cycles 2-6 may be given on the same day as nivolumab for the previous cycle). Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response, partial response, or stable disease proceed to maintenance therapy. MAINTENANCE: Within 6 weeks after the last dose of lenalidomide in induction therapy, patients receive lenalidomide PO daily on days 1-21, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, CT, PET/CT, lumbar puncture, bone marrow aspirate and biopsy, testicular ultrasound and ECHO. (See Detailed Description)

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

Approved in United States as Trexall for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in Canada as Mexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis

Approved in European Union as Methotrexate for:

• Acute lymphoblastic leukemia
• Non-Hodgkin's lymphoma
• Osteosarcoma
• Breast cancer
• Lung cancer
• Head and neck cancer
• Psoriasis
• Rheumatoid arthritis
• Crohn's disease
• Ulcerative colitis

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Rituximab has significantly improved outcomes for patients with Non-Hodgkin's lymphoma (NHL), particularly in aggressive forms like diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL).

The treatment is generally well-tolerated by patients and has been shown to be cost-effective, making it a valuable option in both initial and relapsed cases of B cell NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of non-Hodgkin's lymphoma--a critical evaluation of randomized controlled trials. Griffin, MM., Morley, N.[2020]

Rituximab, when added to standard chemotherapy, significantly improved survival rates in patients with non-Hodgkin's lymphoma.

In patients with chronic B-cell lymphocytic leukemia, the addition of rituximab to fludarabine-based regimens enhanced both response rates and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the safety and feasibility of rapid infusion of rituximab. Atmar, J.[2022]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

Rituximab has shown a response rate of approximately 70% as a first-line treatment for indolent lymphoma, with low toxicity and the ability to retreat patients successfully, leading to longer remission durations.

Combination therapies using rituximab with chemotherapy have resulted in high complete response rates and a greater likelihood of molecular complete remission compared to chemotherapy alone, indicating its potential to enhance treatment outcomes in lymphoid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibody therapy in lymphoid malignancies. Hainsworth, JD.[2019]

In a Phase II trial involving 38 patients with relapsed or refractory low-grade non-Hodgkin's lymphoma, the combination of rituximab and IFN-alpha-2a showed a 45% overall response rate, with 11% achieving a complete response and 34% a partial response.

The treatment was generally well tolerated, with no unexpected toxicities and no grade 4 adverse events reported, although common side effects included fatigue, chills, and fever.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a. Davis, TA., Maloney, DG., Grillo-López, AJ., et al.[2022]

In a study of 51 patients with rheumatoid arthritis, rituximab combined with a TNF inhibitor and methotrexate showed a safety profile similar to previous trials, with only one serious infection reported in the rituximab group.

While there was a slight increase in serious adverse events in the rituximab group, the efficacy did not show a significant advantage over placebo, with ACR20 improvement responses of 30% for rituximab compared to 17% for placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Greenwald, MW., Shergy, WJ., Kaine, JL., et al.[2015]

In a study of 33 patients with aggressive non-Hodgkin's lymphoma, the combination of Rituxan (rituximab) and CHOP chemotherapy resulted in a high overall response rate of 94%, with 61% achieving a complete response.

The treatment was well-tolerated, with common side effects like fever and chills, and did not hinder the completion of the full six-course regimen, indicating both safety and efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Vose, JM., Link, BK., Grossbard, ML., et al.[2022]

A long-term safety evaluation of rituximab in 3194 patients with moderate-to-severe rheumatoid arthritis over 9.5 years showed stable rates of serious adverse events and infections, comparable to those receiving placebo plus methotrexate.

The study found no increased risk of malignancy or significant adverse events with prolonged rituximab exposure, indicating that it is generally well tolerated even after multiple treatment courses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. van Vollenhoven, RF., Emery, P., Bingham, CO., et al.[2021]

Rituximab, a monoclonal antibody used for treating certain cancers and autoimmune diseases, is generally well tolerated but can cause serious side effects, including rare but life-threatening cardiovascular events like myocardial infarction.

A case study of a 58-year-old man revealed that he experienced a ST-elevation myocardial infarction during rituximab treatment, highlighting the need for careful screening for ischemic heart disease in patients receiving this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature. Sharif, K., Watad, A., Bragazzi, NL., et al.[2022]

Rituximab has been shown to be very safe over more than 10 years of use, but it can significantly increase the risk of infections, especially in patients with low-grade lymphoma or severe immunodeficiency, such as those with HIV or on immunosuppressive therapies.

The most critical infection associated with rituximab is hepatitis B reactivation, which can lead to severe liver failure; therefore, screening for hepatitis B and considering preemptive antiviral treatment is essential for patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab-associated infections. Gea-Banacloche, JC.[2020]

Lenalidomide is an orally bioavailable immunomodulator that has shown significant antitumor activity in treating various types of B-cell lymphomas, including mantle cell lymphoma and diffuse large B-cell lymphoma.

The drug has a favorable safety profile and is effective both as a standalone treatment and in combination with other therapies, marking a shift from traditional chemotherapy approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of lenalidomide in non-Hodgkin lymphoma. Galanina, N., Petrich, A., Nabhan, C.[2019]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rituximab in the treatment of non-Hodgkin's lymphoma--a critical evaluation of randomized controlled trials. [2020]

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

Review of the safety and feasibility of rapid infusion of rituximab. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Monoclonal antibody therapy in lymphoid malignancies. [2019]

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

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a. [2022]

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

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. [2015]

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

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. [2022]

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

Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature. [2022]

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

Rituximab-associated infections. [2020]

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

The evolving role of lenalidomide in non-Hodgkin lymphoma. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. [2021]

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

Lenalidomide in follicular lymphoma. [2021]

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

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. [2022]

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

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