Valemetostat + Rituximab + Lenalidomide for Follicular Lymphoma

Overseen By Loretta Nastoupil, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers, P-gp inducers

Disqualifiers: DLBCL, Grade 3B FL, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

To find a recommended dose of valemetostat that can be given in combination with rituximab and lenalidomide to patients with follicular lymphoma. The safety and effects of this drug combination will also be studied

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have used certain medications like lenalidomide within the past 12 months or if you are currently using specific drugs that affect liver enzymes. It's best to discuss your current medications with the trial team.

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

Research shows that Lenalidomide combined with Rituximab is effective for treating follicular lymphoma, as it significantly prolongs the time patients live without the disease getting worse. This combination is well-tolerated and offers a chemotherapy-free option for patients, including those whose disease has become resistant to Rituximab. ^{1 2 3 4 5}

Is the combination of Lenalidomide and Rituximab safe for treating follicular lymphoma?

The combination of Lenalidomide and Rituximab, known as the R(2) regimen, has a manageable safety profile for treating follicular lymphoma. Common side effects include neutropenia (low white blood cell count), which is usually managed with dose adjustments, and mild skin reactions. Overall, the treatment is considered safe with predictable and manageable side effects. ^{1 3 6 7 8}

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

This treatment is unique because it combines Valemetostat, a novel drug, with the established combination of Lenalidomide and Rituximab, which has shown effectiveness in follicular lymphoma. Valemetostat may offer a new mechanism of action that could enhance the treatment's effectiveness compared to existing options. ^{1 2 4 5 9}

Research Team

Loretta Nastoupil, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with previously treated, relapsed or refractory follicular lymphoma (grades 1-3A) who need systemic therapy. Participants must have measurable disease, be in good physical condition (ECOG ≤2), and have proper kidney, liver, and bone marrow function. Women of childbearing potential must use effective birth control methods.

Inclusion Criteria

My kidney function, measured by creatinine clearance, meets the trial's requirement.

I have a tumor larger than 2 cm that has not been treated with radiation.

Subjects must meet all of the eligibility criteria to be enrolled on this study.

Exclusion Criteria

My condition has progressed to diffuse large B-cell lymphoma.

I am not pregnant, breastfeeding, and do not have heart issues or infections.

My condition is Grade 3B Follicular Lymphoma.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Evaluate the safety and tolerability of valemetostat in combination with R2 and determine the recommended phase 2 dose

8-12 weeks

Phase 2 Evaluation

Evaluate the efficacy of valemetostat in combination with R2 in relapsed or refractory follicular lymphoma

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Lenalidomide
• Rituximab
• Valemetostat

Trial Overview The trial is testing the combination of valemetostat with rituximab and lenalidomide to determine a safe dosage and assess its effects on patients with follicular lymphoma who have had previous treatments but their disease has returned or did not respond.

Participant Groups

Group I: Phase 1 Dose Escalation Experimental Treatment 3 Interventions

The dose escalation phase will assess the safety/tolerability of escalating doses of valemetostat and lenalidomide when combined with rituximab

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+

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Daiichi Sankyo, Inc.

Industry Sponsor

Trials

390

Recruited

442,000+

Yuki Abe

Daiichi Sankyo, Inc.

Chief Medical Officer since 2022

MD

Hiroyuki Okuzawa

Daiichi Sankyo, Inc.

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

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]

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]

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]

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, 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]

In a large observational study of 2150 patients with relapsed/refractory multiple myeloma, lenalidomide plus dexamethasone demonstrated a favorable safety profile, with lower incidence rates of neuropathy and infections compared to other treatments like bortezomib and thalidomide.

The study confirmed that lenalidomide's safety profile in a real-world setting is consistent with previous clinical trial data, with no new safety concerns identified, although it did show a higher incidence of neutropenia compared to bortezomib and thalidomide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. Gamberi, B., Berthou, C., Hernandez, M., et al.[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]

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

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). [2022]

3. 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]

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

Lenalidomide in follicular lymphoma. [2021]

5. 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]

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]

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

A Noninterventional, Observational, European Post-Authorization Safety Study of Patients With Relapsed/Refractory Multiple Myeloma Treated With Lenalidomide. [2021]

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

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