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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of a new drug combination for treating follicular lymphoma, a type of blood cancer. The study will assess the safety and effectiveness of combining valemetostat (a new potential drug), rituximab, and lenalidomide. Patients whose follicular lymphoma has returned or worsened after previous treatment may be suitable candidates, especially those requiring further systemic therapy due to tumor size or other factors. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

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.

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

Research shows that the combination of valemetostat, rituximab, and lenalidomide is still undergoing safety testing for treating follicular lymphoma. Earlier studies examined valemetostat for certain B-cell lymphomas unresponsive to other treatments. These studies found that valemetostat was generally well-tolerated, though some patients experienced side effects like tiredness and nausea.

Rituximab and lenalidomide already treat various types of lymphoma and have established safety records. Rituximab often causes reactions during infusions, while lenalidomide can lead to low blood cell counts and tiredness.

Since this study is in its early stages, it aims to determine the safest dose of valemetostat when combined with rituximab and lenalidomide. Researchers are still identifying the best way to use these drugs together safely. Prospective participants should know that early-phase studies primarily focus on assessing safety and dosage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of valemetostat, rituximab, and lenalidomide for follicular lymphoma because it introduces a novel mechanism of action. Unlike standard treatments like chemotherapy and monoclonal antibodies, valemetostat is a dual inhibitor that targets specific proteins involved in cancer cell survival, potentially increasing the effectiveness when used with rituximab and lenalidomide. This approach aims to not only enhance treatment efficacy but also reduce the side effects typically associated with conventional therapies. By combining these agents, there's hope for improved patient outcomes and a new avenue for tackling follicular lymphoma.

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

Research has shown that using lenalidomide with rituximab effectively treats follicular lymphoma, helping patients live longer without disease progression. Valemetostat has shown promise in patients with types of non-Hodgkin lymphomas similar to follicular lymphoma, especially when the disease has returned or resisted other treatments. In this trial, participants will receive a combination of valemetostat, lenalidomide, and rituximab. Although the effectiveness of this three-drug combination is still under investigation, each drug has demonstrated potential against similar cancers, suggesting that using these treatments together might be effective for follicular lymphoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Loretta Nastoupil, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 worsened on lenalidomide or I was treated with it in the last year.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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 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, 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]

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 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]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-00072

Valemetostat in Combination with Lenalidomide and ... This phase I/II trial evaluates the safety, best dose, and effectiveness of valemetostat tosylate (valemetostat) in combination with lenalidomide plus rituximab

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05683171

NCT05683171 | A Phase 1/2, Open ... A Phase 1/​2, Open-label Study of Valemetostat in Combination With Rituximab and Lenalidomide in Relapsed or Refractory Follicular Lymphoma · Study Overview.

3. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1731/500164/Valemetostat-for-Relapsed-or-Refractory-B-Cell

Valemetostat for Relapsed or Refractory B-Cell Lymphomas Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123083349

Valemetostat for Relapsed or Refractory B-Cell Lymphomas The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT ...

5. withpower.com withpower.com/trial/phase-2-lymphoma-5-2023-2b64e

Valemetostat + Rituximab + Lenalidomide for Follicular ... Research shows that Lenalidomide combined with Rituximab is effective for treating follicular lymphoma, as it significantly prolongs the time patients live ...

6. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2022-0551.html

A phase 1/2, open-label study of Valemetostat in ... Study #2022-0551. A phase 1/2, open-label study of Valemetostat in combination with Rituximab and Lenalidomide in relapsed or refractory Follicular Lymphoma.