Combination Therapy for Non-Hodgkin's Lymphoma

Recruiting at 11 trial locations

Overseen By Crystal Miwa

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SWOG Cancer Research Network

Must not be taking: BTK inhibitors, CYP3A inhibitors

Disqualifiers: CNS involvement, MDS, T-LBL, 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: Unknown

227 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase 2 trial studies the side effects and best dose of tazemetostat and zanubrutinib in combination with tafasitamab and lenalidomide, and to see how well these combinations work in treating patients with large B-cell lymphoma that returned or did not respond to earlier treatment. Tazemetostat is in a class of medications called EZH2 inhibitors. It helps to stop the spread of cancer cells. Zanubrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. tafasitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The addition of tazemetostat or zanubrutinib to tafasitamab and lenalidomide may be able to shrink the cancer or extend the time without cancer symptoms coming back.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot be on direct vitamin K inhibitors or strong/moderate CYP3A inhibitors or inducers. Steroid use for lymphoma symptoms is allowed but must be stopped before starting the trial.

What data supports the effectiveness of the drug combination therapy for Non-Hodgkin's Lymphoma?

The combination of tafasitamab and lenalidomide has shown effectiveness in treating relapsed or refractory diffuse large B-cell lymphoma, with a 57.5% overall response rate and a 41.3% complete response rate in a study. This combination therapy is well-tolerated and provides long-term clinical benefits with durable responses. ^{1 2 3 4 5}

Is the combination therapy of tafasitamab and lenalidomide safe for humans?

The combination of tafasitamab and lenalidomide has been studied in patients with diffuse large B-cell lymphoma, showing manageable safety with common side effects including infections, blood disorders, and gastrointestinal issues. The safety profile was consistent over time, with no new safety concerns emerging in long-term studies. ^{1 4 5 6 7}

What makes the combination therapy for Non-Hodgkin's Lymphoma unique?

This combination therapy is unique because it includes tafasitamab, a humanized monoclonal antibody that targets CD19 on B-cells, and is used with lenalidomide, showing promising results in patients with relapsed or refractory diffuse large B-cell lymphoma who are not eligible for stem cell transplantation. The therapy has demonstrated long-term clinical benefits and durable responses, making it a novel option for patients with limited treatment choices. ^{1 4 5 7 8}

Research Team

Jennifer E Amengual

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

Adults with high-grade B-cell lymphoma that has returned or is resistant to treatment can join this trial. They must have had 1-5 prior treatments, be in relatively good health based on specific blood and liver function tests, and not be pregnant or breastfeeding. People with central nervous system involvement, allergies to the drugs used, certain other cancers, or those who are candidates for stem cell transplant are excluded.

Inclusion Criteria

I can take care of myself, but I might not be able to do heavy physical work.

I have grade 3B Follicular lymphoma.

My large B-cell lymphoma has come back or didn't respond to treatment, as confirmed by tests.

Exclusion Criteria

My cancer has not spread to my brain or spinal cord.

I have never taken BTK inhibitors or tazemetostat.

I have never been treated with tafasitamab or lenalidomide.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Patients receive tafasitamab, lenalidomide, and either tazemetostat or zanubrutinib to determine the recommended phase II dose

8-12 weeks

Regular visits for drug administration and monitoring

Randomized Phase II Study

Patients are randomized to receive tafasitamab, lenalidomide, and either tazemetostat or zanubrutinib, or control treatment

Up to 3 years

Regular visits for drug administration, PET/CT, and MRI scans

Follow-up

Participants are monitored for progression-free survival and overall survival

Up to 3 years

Periodic follow-up visits

Treatment Details

Interventions

• Lenalidomide
• Tafasitamab
• Tazemetostat
• Zanubrutinib

Trial Overview The trial is testing a combination of tazemetostat (an EZH2 inhibitor), zanubrutinib (a kinase inhibitor), tafasitamab (a monoclonal antibody), and lenalidomide (an immunomodulatory agent) against large B-cell lymphoma. It aims to find the best dose and see how well these drugs work together after previous treatments failed.

Participant Groups

Group I: Part II, Arm III (tafasitamab, lenalidomide, zanubrutinib) Experimental Treatment 9 Interventions

Patients receive tafasitamab IV, lenalidomide PO, and zanubrutinib PO on study. Patients also undergo PET/CT and CT or MRI scans throughout the trial. Patients also have the option to undergo collection of blood samples during screening and on study.

Group II: Part II, Arm I (tafasitamab, lenalidomide, tazemetostat) Experimental Treatment 9 Interventions

Patients receive tafasitamab IV, lenalidomide PO, and tazemetostat PO on study. Patients also undergo PET/CT and CT or MRI scans throughout the trial. Patients also have the option to undergo collection of blood samples during screening and on study.

Group III: Part I, Arm III (tafasitamab, lenalidomide, zanubrutinib) Experimental Treatment 9 Interventions

Patients receive tafasitamab IV, lenalidomide PO, and zanubrutinib PO on study. Patients also undergo PET/CT and CT or MRI scans throughout the trial. Patients also have the option to undergo collection of blood samples during screening and on study.

Group IV: Part I, Arm I (tafasitamab, lenalidomide, tazemetostat) Experimental Treatment 8 Interventions

Patients receive tafasitamab IV, lenalidomide PO, and tazemetostat PO on study. Patients also undergo PET/CT and CT or MRI scans throughout the trial. Patients also have the option to undergo collection of blood samples during screening and on study.

Group V: Part II, Arm II (tafasitamab, lenalidomide) Active Control 8 Interventions

Patients receive tafasitamab IV and lenalidomide PO on study. Patients also undergo PET/CT and CT or MRI scans throughout the trial. Patients also have the option to undergo collection of blood samples during screening and on study.

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?

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

In the final 5-year analysis of the L-MIND study involving 80 patients with relapsed/refractory diffuse large B-cell lymphoma, the combination of tafasitamab and lenalidomide showed a significant objective response rate of 57.5%, with a complete response rate of 41.3%.

The treatment demonstrated long-term clinical benefits, with a median overall survival of 33.5 months and manageable adverse events, indicating that this immunotherapy combination is both effective and well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety in the phase II L-MIND study. Duell, J., Abrisqueta, P., Andre, M., et al.[2023]

In the phase II L-MIND study, tafasitamab combined with lenalidomide showed a 57.5% objective response rate in patients with relapsed/refractory diffuse large B-cell lymphoma, with a complete response in 40% of patients after more than 35 months of follow-up.

The treatment demonstrated a median overall survival of 33.5 months and a median duration of response of 43.9 months, with no unexpected toxicities, indicating a favorable safety and efficacy profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Duell, J., Maddocks, KJ., González-Barca, E., et al.[2021]

Tafasitamab plus lenalidomide (TAFA + LEN) showed significantly better overall survival (OS) and progression-free survival (PFS) compared to standard treatments like polatuzumab vedotin + bendamustine + rituximab (POLA + BR) and bendamustine + rituximab (BR) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

The study found that TAFA + LEN was associated with longer duration of response (DOR) and higher complete response rates (CRR), indicating its potential as a more effective treatment option, although further validation through large randomized trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab Plus Lenalidomide Versus 3 Rituximab-Based Treatments for Non-Transplant Eligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Matching-Adjusted Indirect Comparison. Cordoba, R., Prawitz, T., Westley, T., et al.[2022]

Tafasitamab, an anti-CD19 monoclonal antibody, received accelerated approval in July 2020 for treating adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in combination with lenalidomide, marking it as the first second-line therapy approved for this patient group in the USA.

The drug is administered intravenously at a recommended dose of 12 mg per kg and is also being explored for use in other B-cell malignancies, indicating its potential versatility in treating various types of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab: First Approval. Hoy, SM.[2022]

In a phase 2 study involving 81 patients with relapsed or refractory diffuse large B-cell lymphoma, the combination of tafasitamab and lenalidomide resulted in a 60% objective response rate, with 43% achieving a complete response, indicating significant antitumor activity.

The treatment was generally well tolerated, although serious adverse events occurred in 51% of patients, with neutropenia being the most common, suggesting that while effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Salles, G., Duell, J., González Barca, E., et al.[2020]

In a phase 1b study involving 66 adults with untreated diffuse large B-cell lymphoma (DLBCL), the combination of tafasitamab with R-CHOP showed promising efficacy, with an end-of-treatment overall response rate of 75.8% and a complete response rate of 72.7%.

The safety profile was manageable, with most treatment-emergent adverse events being grade 1 or 2, although higher rates of grade ≥3 neutropenia and thrombocytopenia were observed in the group receiving tafasitamab with lenalidomide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study. Belada, D., Kopeckova, K., Bergua Burgues, JM., et al.[2023]

Tafasitamab, a monoclonal antibody targeting CD19, showed a significant objective response rate of 56.8% in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) during the L-MIND clinical trial, with a median duration of response of 34.6 months.

The treatment was associated with notable adverse events, particularly infections (72.8% of patients) and blood disorders (65.4%), indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Tafasitamab in Combination With Lenalidomide for the Treatment of Adult Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma. Delgado, J., Papadouli, I., Sarac, SB., et al.[2021]

A patient with relapsed/refractory diffuse large B-cell lymphoma and end-stage renal disease on hemodialysis achieved a complete response after treatment with tafasitamab and reduced-dose lenalidomide, indicating potential efficacy in this challenging population.

The therapy was well tolerated, with the only significant side effect being grade 4 neutropenia, which was managed by adjusting the lenalidomide dose, suggesting that tafasitamab can be safely administered in patients undergoing hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafasitamab and lenalidomide for relapsed/refractory diffuse large B-cell lymphoma in a patient on chronic intermittent hemodialysis. Moore, DC., Eagers, KA., Janes, A., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety in the phase II L-MIND study. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. [2021]

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

Tafasitamab Plus Lenalidomide Versus 3 Rituximab-Based Treatments for Non-Transplant Eligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Matching-Adjusted Indirect Comparison. [2022]

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

Tafasitamab: First Approval. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. [2020]

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

Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study. [2023]

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

The European Medicines Agency Review of Tafasitamab in Combination With Lenalidomide for the Treatment of Adult Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma. [2021]

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

Tafasitamab and lenalidomide for relapsed/refractory diffuse large B-cell lymphoma in a patient on chronic intermittent hemodialysis. [2022]