Combination Therapy for B-Cell Lymphoma

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Plasmablastic lymphoma, Active infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-17 cycles (28 days per cycle)

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—mosunetuzumab (a targeted therapy), polatuzumab vedotin (a targeted therapy), and lenalidomide (an immunomodulatory drug)—to determine the optimal dose and understand side effects in patients with diffuse large B-cell lymphoma (DLBCL) that has returned or not responded to previous treatments. The treatment aims to stop cancer cells from growing and spreading by using targeted therapies and boosting the immune system. It suits patients with relapsed or refractory DLBCL who have tried at least one previous treatment and have measurable disease by scan. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, some concurrent cancer therapies are allowed, so it's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Past studies have shown that the combination of mosunetuzumab, polatuzumab vedotin, and lenalidomide is safe for treating B-cell lymphoma. Research indicates that most patients tolerate this treatment well. Although some side effects occurred, they were usually manageable. These drugs work together to target cancer cells and boost the immune system's ability to fight cancer. While there is some risk of side effects, the treatment shows promise, particularly for patients who cannot undergo a transplant. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination therapy for B-cell lymphoma because it brings together three powerful treatments—lenalidomide, mosunetuzumab, and polatuzumab vedotin—in a novel way. While standard treatments often involve chemotherapy and targeted therapies like rituximab, this combo offers a unique multi-targeted approach. Mosunetuzumab is a bispecific antibody that helps the immune system directly target and kill cancer cells, while polatuzumab vedotin delivers a toxic payload specifically to B-cells. Lenalidomide boosts the immune response against cancer. This innovative strategy aims to enhance effectiveness and potentially improve outcomes for patients with B-cell lymphoma.

What evidence suggests that this trial's treatments could be effective for relapsed/refractory diffuse large B-cell lymphoma?

This trial will evaluate the combination of mosunetuzumab, polatuzumab vedotin, and lenalidomide for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Studies have shown that using mosunetuzumab and polatuzumab vedotin together can be effective. Mosunetuzumab helps the immune system find and destroy cancer cells, while polatuzumab vedotin targets specific cancer cells and delivers a toxic substance to kill them. Lenalidomide, another part of this treatment, strengthens the immune system and stops cancer cells from growing. Research indicates that this combination leads to strong, long-lasting responses in patients, making it a promising option for those whose cancer has returned or not responded to previous treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Joseph M. Tuscano

Principal Investigator

City of Hope Comprehensive Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with Diffuse Large B-Cell Lymphoma that has returned or didn't respond to previous treatments. They should have a life expectancy of at least 12 weeks, measurable disease by scans, and an ECOG performance status of 2 or better. Patients who've had CAR T-cell therapy or relapsed after other therapies may join, except those under 18 years old.

Inclusion Criteria

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

My DLBCL has not improved after at least one treatment, except if I'm getting CAR T therapy as my second treatment and have a specific score.

Cohort A must have had an incomplete response or Deauville score of 3 or 4 at 90 days post CAR-T therapy, while cohort B comprises patients who relapsed after one or more previous treatment regimens (for example relapse following day 90 from CAR-T, or those that experienced recurrence on other therapies but were ineligible for either CAR-T or autologous hematopoietic cell transplantation).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mosunetuzumab, polatuzumab vedotin, and lenalidomide. Mosunetuzumab is administered IV on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Polatuzumab vedotin is administered IV on day 1 for 6 cycles. Lenalidomide is taken orally on days 1-21 for 8 cycles in patients who achieve CR or up to 17 cycles.

8-17 cycles (28 days per cycle)

Multiple visits for IV administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes PET/CT scans and blood sample collection.

Every 3-6 months for 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Mosunetuzumab
• Polatuzumab Vedotin

Trial Overview The trial tests a combination of three drugs: Mosunetuzumab, Polatuzumab Vedotin, and Lenalidomide in patients with relapsed/refractory DLBCL. It aims to find the safest doses and observe how well these drugs work together against cancer cells.

How Is the Trial Designed?

Group I: Treatment (mosunetuzumab, polatuzumab vedotin, lenalidomide) Experimental Treatment 6 Interventions

Patients receive mosunetuzumab IV over 2-4 hours on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Treatment repeats every 28 days for 8 cycles in patients who achieve a CR or up to 17 cycles for patients with a PR or SD in the absence of disease progression or unacceptable toxicity. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 for 6 cycles and lenalidomide PO on days 1-21 for 8 cycles in patients who achieve CR or up to 17 cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET/CT and blood sample collection throughout the 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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

The Pola-G-Len combination therapy demonstrated a high complete response rate of 63% and an overall objective response rate of 76% in patients with relapsed or refractory follicular lymphoma, indicating its potential efficacy in this challenging patient population.

The study identified a recommended phase 2 dose of 1.4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide, with manageable safety profiles, although common adverse events included neutropenia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Diefenbach, C., Kahl, BS., McMillan, A., et al.[2022]

Polatuzumab vedotin (PV) is an innovative antibody-drug conjugate that has been approved by the US FDA for treating refractory/relapsed diffuse large B-cell lymphoma, particularly in patients who are not eligible for stem cell transplants.

In a pivotal Phase II trial, PV demonstrated significant efficacy and an acceptable safety profile when used in combination with bendamustine and rituximab, highlighting its potential as a valuable treatment option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin, an anti-CD79b antibody-drug conjugate for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Camus, V., Tilly, H.[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]

The study evaluated the antibody-drug conjugate polatuzumab vedotin (pola) combined with rituximab/obinutuzumab and chemotherapy in treating B-cell non-Hodgkin lymphoma, showing that pola's pharmacokinetics were consistent and dose-proportional across different treatment cycles.

There were no significant drug-drug interactions between pola and the chemotherapy regimen (R/G-CHP), indicating that pola can be safely used in combination with these treatments for previously untreated diffuse large B-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma. Shemesh, CS., Agarwal, P., Lu, T., 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]

Polatuzumab vedotin (POLIVY®) is an effective treatment for adult patients with diffuse large B-cell lymphoma, approved after showing significant anti-cancer activity by delivering a potent drug directly to B cells.

The incidence of anti-drug antibodies (ADA) against polatuzumab vedotin is low, likely due to its mechanism of action that targets and kills B cells, which minimizes immune response and supports a favorable benefit/risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Dere, RC., Beardsley, RL., Lu, D., et al.[2023]

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, has been approved for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients who are ineligible for transplant, showing a complete response rate of 40% compared to 18% for standard treatment with bendamustine and rituximab (BR).

The most common side effects associated with polatuzumab vedotin treatment include cytopenias (a reduction in blood cells) and peripheral neuropathy, highlighting the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin to treat relapsed or refractory diffuse large B-cell lymphoma, in combination with bendamustine plus rituximab. Amaya, ML., Jimeno, A., Kamdar, M.[2021]

In a phase 1b/2 trial involving 120 patients with relapsed/refractory aggressive large B cell lymphoma, the combination of mosunetuzumab and polatuzumab vedotin achieved a high overall response rate of 59.2% and a complete response rate of 45.9%, indicating strong efficacy as a second-line therapy.

The treatment demonstrated a favorable safety profile, with the most common serious side effects being neutropenia (25%) and fatigue (6.7%), and only 16.7% of patients experiencing any-grade cytokine release syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial. Budde, LE., Olszewski, AJ., Assouline, S., et al.[2023]

In a study of 57 patients with relapsed large B-cell lymphoma after CAR T-cell therapy, polatuzumab vedotin (PV) showed a response rate of 44%, with 14% achieving complete remission, indicating its potential efficacy in this challenging patient population.

The median progression-free survival was only 10 weeks, and factors like bone marrow involvement and high lactate dehydrogenase levels were linked to shorter survival, highlighting the need for further research on treatment resistance and consolidation strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter retrospective study of polatuzumab vedotin in patients with large B-cell lymphoma after CAR T-cell therapy. Gouni, S., Rosenthal, AC., Crombie, JL., et al.[2023]

Polatuzumab vedotin, when combined with bendamustine and rituximab (polatuzumab-BR), is an effective treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), offering a new therapeutic avenue for those who do not respond to standard treatments.

This combination therapy is considered safe and is particularly beneficial for transplant-ineligible patients, with ongoing trials exploring its use alongside other treatments like CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of polatuzumab vedotin for the treatment of patients with diffuse large B-cell lymphoma. Walji, M., Assouline, S.[2021]

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, has demonstrated significant clinical effectiveness in treating follicular and diffuse large B-cell lymphoma (DLBCL), and is FDA-approved for use with bendamustine and rituximab in patients with relapsed or refractory DLBCL.

The review highlights the ongoing research and potential future applications of polatuzumab in the treatment of B-cell non-Hodgkin lymphoma, indicating its importance in expanding treatment options for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of Polatuzumab Vedotin in the Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma: A Brief Report on the Emerging Clinical Data. Sawalha, Y., Maddocks, K.[2022]

In a study involving 85 patients with untreated diffuse large B-cell lymphoma, the combination of polatuzumab vedotin with standard chemotherapy (R-CHP or G-CHP) showed promising preliminary efficacy, with 89% of patients achieving an overall response and 77% achieving a complete response.

The safety profile of polatuzumab vedotin was manageable, with common adverse events including neutropenia and peripheral neuropathy, leading to the establishment of a recommended phase 2 dose of 1.8 mg/kg for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Tilly, H., Morschhauser, F., Bartlett, NL., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06015880

NCT06015880 | Testing the Combination of Anti-cancer ... This phase I trial studies the side effects and best dose of mosunetuzumab when given together with polatuzumab vedotin and lenalidomide in treating patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10803244/

Mosunetuzumab with polatuzumab vedotin in relapsed or ... These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/mosunetuzumab?pn=1

Clinical Trials Using Mosunetuzumab - NCI Low Dose Mosunetuzumab for the Treatment of Patients with Indolent B-Cell Lymphoma ... Lenalidomide for the Treatment of Relapsed B-Cell Non-Hodgkin's Lymphoma.

4. gene.com gene.com/media/press-releases/15088/2025-11-03/genentech-to-present-new-data-from-its-b

Genentech: Press Releases | Monday, Nov 3, 2025 Data from innovative pipeline signals progress toward improved outcomes in hemophilia A, lymphoma, and multiple myeloma. South San Francisco, CA ...

5. ascopubs.org ascopubs.org/doi/pdfdirect/10.1200/JCO-25-01957

Mosunetuzumab plus polatuzumab vedotin in transplant- ... outcomes were improved compared with R-GemOx. 85. CONCLUSION: Mosun-Pola demonstrated superior efficacy verus R-GemOx, with significant. 86.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05615636

NCT05615636 | A Phase II Trial of Mosunetuzumab ... Participants will receive mosunetuzumab, polatuzumab vedotin, tafasitamab, and lenalidomide at the dose level that was found tolerated in the safety run-in.

7. uvahealth.com uvahealth.com/clinical-trials/trial/301211

A phase 1 study of mosunetuzumab with polatuzumab ... ... B-cell lymphoma. The purpose of this study is to test the safety of 3 drugs taken in combination called lenalidomide, mosunetuzumab, and polatuzumab vedotin.

8. nature.com nature.com/articles/s41591-023-02726-5

Mosunetuzumab with polatuzumab vedotin in relapsed or ... Mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible ...

9. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06477

Testing the Combination of Anti-cancer Drugs ... Giving mosunetuzumab with polatuzumab vedotin and lenalidomide may work better in treating patients with relapsed/refractory DLBCL. Eligibility Criteria ...

10. ascopubs.org ascopubs.org/doi/pdf/10.1200/JCO-25-01957

Mosunetuzumab plus polatuzumab vedotin in transplant- ... B-cell lymphoma: primary results of the phase 3 SUNMO trial. Lihua E ... mosunetuzumab SC plus polatuzumab vedotin demostrates improved outcomes ...