Tazemetostat + Lenalidomide + Rituximab for Follicular Lymphoma

(SYMPHONY-1 Trial)

Recruiting at 247 trial locations

Overseen By Ipsen Clinical Study Enquiries

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Epizyme, Inc.

Must be taking: Lenalidomide

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Prior tazemetostat, Lenalidomide, Brain metastases, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

612 Participants Needed

Trial Summary

What is the purpose of this trial?

The participants of this study would have relapsed/refractory follicular lymphoma. Follicular lymphoma is a type of blood cancer. It is referred to as 'relapsed' when the disease has come back after a period of improvement after that follows a treatment regimen and 'refractory' when treatment no longer works. Stage 1 of this trial will study the safety and the level that adverse effects of each of the study drug combinations can be tolerated (known as tolerability). It is also designed to establish a recommended study drug dosage for stage 2 and 3. Stage 1 of the study is completed. Stages 2 and 3 will evaluate and compare how long participants live without their disease getting worse when receiving the study drug in combination with other drug treatment versus the placebo (dummy drug) in combination with other drug treatment.

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 take medications that are strong CYP3A inhibitors or inducers, and you should avoid grapefruit products. There are also specific time requirements between your last anticancer therapy and the start of the trial.

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

Lenalidomide combined with Rituximab has shown an acceptable safety profile in treating follicular lymphoma, with manageable side effects like neutropenia (low white blood cell count) that can be controlled with dosage adjustments. Non-severe side effects such as fatigue and rash are generally manageable, and the combination is considered safe for use in humans. ^{1 2 3 4 5}

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

This drug combination is unique because it includes Tazemetostat, which is an EZH2 inhibitor that targets specific genetic mutations in cancer cells, potentially enhancing the effectiveness of Lenalidomide and Rituximab, which are already known to be effective in treating follicular lymphoma. This combination aims to provide a more targeted approach to treatment, potentially improving outcomes for patients with this condition. ^{1 6 7 8 9}

Research Team

Ipsen Medical Director

Principal Investigator

Ipsen

Eligibility Criteria

Adults with relapsed/refractory follicular lymphoma who've had prior treatments can join. They need good liver and kidney function, no major illnesses or brain metastases, not pregnant or breastfeeding, and must use effective contraception. Excluded are those with certain viral infections, recent major surgery, severe allergies to trial drugs, or taking specific medications.

Inclusion Criteria

I am a man who will use a condom or abstain from sex during and for 3 months after the study.

I had hepatitis but my liver functions are normal and my virus levels are undetectable.

All study participants enrolled must be registered into the mandatory Revlimid REMS™ program for the US or Revlimid Global PPP for ex-US and be willing and able to comply with the requirements of the Revlimid REMS™ or Revlimid Global PPP program as appropriate for the country in which the drug is being used

Exclusion Criteria

I have a serious heart condition.

I am currently being treated for an infection with medication.

I am not taking strong medications that affect liver enzymes or St. John's wort.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stage 1: Safety Run-in

Evaluate the safety and tolerability of tazemetostat and R2 combination, establish recommended dosage for subsequent stages

Completed

Stage 2: Efficacy and Safety

Assess efficacy and safety in patients with and without EZH2 mutation, includes interim analyses

Up to 96 months

Maintenance Therapy

Tazemetostat or placebo administered as monotherapy for up to 2 years after initial combination therapy

Up to 24 months

Stage 3: Long-term Follow-up

Monitor patients for response and overall survival, follow-up until 5 years post last patient enrollment

Up to 60 months

Treatment Details

Interventions

• Lenalidomide
• Rituximab
• Tazemetostat

Trial Overview The study tests Tazemetostat's effectiveness combined with Lenalidomide and Rituximab versus a placebo combination in improving survival without disease progression. Stage 1 focuses on safety and dosage; stages 2 and 3 compare the drug's efficacy against a placebo.

Participant Groups

Group I: Tazemetostat + R2 arm Experimental Treatment 3 Interventions

Stage 1 (Phase 1b): This phase is now completed. * Tazemetostat was escalated from a starting dose of 400 mg PO twice daily to 600 mg PO twice daily to 800 mg PO twice daily in 28-day cycles. * Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. * Lenalidomide 20 mg or 10 mg (if creatinine clearance ≥60 mL/minute or \<60 mL/minute), administred PO QD on days 1 to 21 for 12 cycles. Stage 2: * Tazemetostat 800 mg administered PO twice daily in continuous 28-day cycles. * Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. * Lenalidomide 20 mg or 10 mg (if creatinine clearance ≥60 mL/minute or \<60 mL/minute), PO QD on days 1 to 21 for 12 cycles. Maintenance Therapy (Stages 1 and 2): Tazemetostat will be administered as monotherapy at an 800 mg twice daily dose for up to 2 years after the initial 12 months of combination therapy.

Group II: Placebo + R2 Arm Placebo Group 3 Interventions

Stage 2: * Placebo administered PO twice daily in continuous 28-day cycles. * Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1; then on day 1 of cycles 2 to 5. * Lenalidomide 20 mg or 10 mg (if creatinine clearance ≥60 mL/minute or \<60 mL/minute), administered PO QD on days 1 to 21 for 12 cycles. Maintenance Therapy (Stage 2): Placebo will be administered as monotherapy twice daily dose for up to 2 years after the initial 12 months of combination therapy. During maintenance, placebo will be continued until disease progression or unacceptable toxicity, or participant withdraws consent.

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?

Epizyme, Inc.

Lead Sponsor

Trials

34

Recruited

2,800+

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 263 patients with relapsed/refractory multiple myeloma, the ixazomib-lenalidomide-dexamethasone (IRd) combination showed a high overall response rate of 73% and a median progression-free survival of 21.2 months, indicating its effectiveness in routine clinical practice.

However, the treatment also had notable safety concerns, with 17% of patients requiring dose reductions for ixazomib and 36% for lenalidomide, and 32% of patients discontinuing ixazomib and 30% discontinuing lenalidomide due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma. Hájek, R., Minařík, J., Straub, 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]

In a study of 90 patients with relapsed/refractory multiple myeloma, the combination of ixazomib, thalidomide, and dexamethasone showed a 51.1% overall response rate, indicating significant efficacy in treating this condition.

The treatment was well tolerated, with rare occurrences of severe toxicities, and ixazomib maintenance therapy improved response depth in 12.4% of patients, suggesting a beneficial long-term effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma. Ludwig, H., Poenisch, W., Knop, S., et al.[2021]

In a phase I study involving 21 elderly patients with untreated diffuse large B-cell lymphoma, the combination of lenalidomide and standard chemotherapy resulted in a high overall response rate of 90%, with 81% achieving complete remission.

The maximum tolerated dose of lenalidomide was determined to be 15 mg/day, with manageable safety concerns, including hematologic toxicities like neutropenia in 28% of treatment courses, indicating that this regimen is safe for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Chiappella, A., Tucci, A., Castellino, A., 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 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]

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 2 study involving 89 patients with relapsed or refractory follicular lymphoma, 79% achieved an overall response after treatment with lenalidomide and obinutuzumab, demonstrating significant efficacy in this patient population.

The treatment had a manageable safety profile, with common adverse events including neutropenia and asthenia, and serious adverse events reported in 34% of patients, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Morschhauser, F., Le Gouill, S., Feugier, P., et al.[2019]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma. [2021]

3. 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]

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

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma. [2021]

5. Italy pubmed.ncbi.nlm.nih.gov

Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. [2021]

6. 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]

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

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

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

Lenalidomide in follicular lymphoma. [2021]

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

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. [2019]