Combination Immunotherapy for Non-Hodgkin's Lymphoma

Overseen By Robby Friedman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Lazaros Lekakis

Must not be taking: Antiepileptics, Immunosuppressants, Anticoagulants, others

Disqualifiers: CNS lymphoma, Uncontrolled infection, Autoimmune disorders, 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: 13

22 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to test if a combination treatment of chimeric antigen receptor (CAR) T-cell therapy, Mosunetuzumab, and Polatuzumab Vedotin will result in tumor reduction.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that systemic immunosuppressive agents and certain biologic agents or chemotherapy are not allowed within specific time frames before starting the trial treatment. It's best to discuss your current medications with the trial team to understand any necessary adjustments.

What data supports the effectiveness of the drug polatuzumab vedotin for treating non-Hodgkin's lymphoma?

Polatuzumab vedotin has shown significant clinical activity and an acceptable safety profile in treating relapsed or refractory B-cell non-Hodgkin's lymphoma, particularly when combined with other therapies like rituximab and bendamustine, leading to its approval for use in patients who have tried at least two other treatments. ^{1 2 3 4 5}

What safety data exists for CAR-T cell therapy in humans?

CAR-T cell therapy has been associated with some serious side effects, including cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects can be more severe in patients with a high tumor burden (large amount of cancer). Efforts are ongoing to improve the safety of this treatment. ^{6 7 8 9 10}

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

This treatment is unique because it combines CAR-T cell therapy, which uses modified immune cells to target cancer, with polatuzumab vedotin, an antibody-drug conjugate that delivers a toxin directly to cancer cells, and mosunetuzumab, which helps activate the immune system against the cancer. This combination aims to enhance the effectiveness of treatment by using different mechanisms to attack the lymphoma. ^{1 2 3 4 11}

Research Team

Lazaros Lekakis

Principal Investigator

University of Miami

Eligibility Criteria

Adults aged 18-80 with aggressive Non-Hodgkin's Lymphoma that is resistant or has returned after treatment. They must have at least one measurable lesion, be in relatively good health (ECOG 0-2), and meet specific blood count criteria. Women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

Signed informed consent and compliance with study requirements

I have at least one lymphoma lesion that can be measured.

My condition is primary mediastinal B cell lymphoma.

Exclusion Criteria

I do not have severe heart disease.

You have an immune system disorder that is not related to the study.

My high blood pressure is not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Phase

Participants receive Mosunetuzumab on Days -42, -35, -28, and -7; and Polatuzumab on Day -28. Evaluation in clinic on Day -6.

5 weeks

5 visits (in-person)

CAR-T Treatment Phase

Participants receive lymphodepleting chemotherapy for three consecutive days beginning on Day -5, followed by CAR-T Cell therapy via infusion on Day 0.

1 week

4 visits (in-person)

Consolidation Phase

Participants receive Mosunetuzumab on Day +14; and combination Mosunetuzumab and Polatuzumab on Days +35, +56, and +77.

13 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Treatment Details

Interventions

• CAR-T Cell Therapy
• Mosunetuzumab
• Polatuzumab

Trial Overview The trial tests if combining CAR-T Cell Therapy with Mosunetuzumab and Polatuzumab can shrink tumors in patients whose lymphoma didn't respond to previous treatments or came back after such treatments, including stem cell transplantation.

Participant Groups

Group I: Combination CAR-T Cell Therapy, Mosunetuzumab + Polatuzumab Experimental Treatment 3 Interventions

Participants will receive study treatment in three phases: Induction Phase, CAR-T Treatment Phase and Consolidation Phase. During the Induction Phase (Days -42, through -6), participants will receive Mosunetuzumab on Days -42, -35, -28, and -7; and Polatuzumab on Day -28. On Day -6, participants will be evaluated in clinic. During the CAR-T Treatment Phase (Days -5, through Day 0), participants will receive lymphodepleting chemotherapy for three consecutive days beginning on Day -5, followed by CAR-T Cell therapy via infusion on Day 0. During the Consolidation Phase (Days +1 through +90), participants will receive Mosunetuzumab on Day +14; and combination Mosunetuzumab and Polatuzumab on Days +35, +56 and +77.

CAR-T Cell Therapy is already approved in United States, European Union for the following indications:

Approved in United States as CAR-T Cell Therapy for:

• Relapsed or refractory large B-cell lymphoma (LBCL)
• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
• Relapsed or refractory mantle cell lymphoma (MCL)
• Relapsed or refractory multiple myeloma (MM)
• Relapsed or refractory follicular lymphoma (FL)

Approved in European Union as CAR-T Cell Therapy for:

• Relapsed or refractory large B-cell lymphoma (LBCL)
• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)
• Relapsed or refractory mantle cell lymphoma (MCL)
• Relapsed or refractory multiple myeloma (MM)
• Relapsed or refractory follicular lymphoma (FL)

Who Is Running the Clinical Trial?

Lazaros Lekakis

Lead Sponsor

Trials

1

Recruited

20+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

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]

Polatuzumab vedotin, an antibody-drug conjugate targeting CD79b, shows promise in treating relapsed or refractory B-cell non-Hodgkin lymphomas, particularly when combined with rituximab and bendamustine, as indicated by early clinical data.

The ongoing phase III POLARIX trial is exploring its effectiveness in first-line treatment for untreated patients, with careful management of dosing to minimize the risk of peripheral neuropathy, potentially making it a key player in DLBCL therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin: an investigational anti-CD79b antibody drug conjugate for the treatment of diffuse large B-cell lymphoma. Bourbon, E., Salles, G.[2022]

Polatuzumab vedotin, an antibody-drug conjugate, demonstrated an acceptable safety profile in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL), with a recommended phase 2 dose of 2.4 mg/kg showing objective responses in 23 out of 42 evaluable patients.

In contrast, the treatment was not effective for patients with chronic lymphocytic leukaemia (CLL), as no objective responses were observed, highlighting the need for further assessment of polatuzumab vedotin specifically in NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Palanca-Wessels, MC., Czuczman, M., Salles, G., et al.[2018]

Polatuzumab vedotin is an antibody-drug conjugate that has shown significant clinical activity and an acceptable safety profile in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL), particularly when combined with anti-CD20 monoclonal antibodies and chemotherapy.

The recent POLARIX trial suggests that polatuzumab may also be effective in frontline treatment for DLBCL, potentially changing its role in managing patients who have not responded to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma. Varma, G., Wang, J., Diefenbach, C.[2022]

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]

CAR T-cell therapy represents a significant advancement in treating aggressive B-cell lymphomas and acute lymphoblastic leukemia, with the first products approved in Europe in 2018, showing long-lasting benefits as a living drug.

While CAR T-cell therapy is effective, it comes with challenges such as high costs, complex administration, and potential severe side effects like cytokine release syndrome and neurotoxicity, prompting ongoing research to enhance its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy. Subklewe, M., von Bergwelt-Baildon, M., Humpe, A.[2020]

Nivolumab and ipilimumab, two FDA-approved immunotherapeutic agents targeting PD-1 and CTLA-4, are effective in treating various cancers but can cause significant immune-related adverse effects (irAEs).

In a case study of a 66-year-old female patient, steroid-resistant colitis induced by these checkpoint inhibitors was successfully treated with infliximab, highlighting a potential management strategy for severe irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. Tidwell, C., Gutnik, S.[2020]

Chimeric antigen receptor (CAR) T-cell therapies have shown promising results in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma, offering complete and lasting clinical responses where traditional therapies have failed.

Four CD19-directed CAR T-cell therapies have been approved by the FDA for specific types of relapsed or refractory lymphomas, indicating a significant advancement in treatment options for these challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapsed/Refractory Non-Hodgkin Lymphoma: Engineering T-Cells to Express Chimeric Antigen Receptors (CARs), a Salvage? Kanwal, B.[2021]

An elderly male patient on pembrolizumab developed four autoimmune toxicities, including type 1 diabetes and pneumonitis, highlighting the risk of multiple immune-related adverse events associated with this treatment.

The case suggests that aging may increase susceptibility to these adverse effects, necessitating close monitoring and prompt management, including stopping the immunotherapy and using steroids for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. Kethireddy, N., Thomas, S., Bindal, P., et al.[2021]

CAR T cell therapy, particularly with the approval of tisagenlecleucel, has shown remarkable efficacy in treating pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia, with six therapies approved as of April 2023 for B-cell malignancies and multiple myeloma.

However, the therapy is associated with significant adverse events like cytokine release syndrome, which are more severe with higher pretreatment tumor burdens; thus, initiating therapy early or using a debulking strategy may help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From bench to bedside: the history and progress of CAR T cell therapy. Mitra, A., Barua, A., Huang, L., et al.[2023]

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]

References

1. England 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. [2023]

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

Polatuzumab vedotin: an investigational anti-CD79b antibody drug conjugate for the treatment of diffuse large B-cell lymphoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. [2018]

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

Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Integrated summary of immunogenicity of polatuzumab vedotin in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy. [2020]

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

Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab. [2020]

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

Relapsed/Refractory Non-Hodgkin Lymphoma: Engineering T-Cells to Express Chimeric Antigen Receptors (CARs), a Salvage? [2021]

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

Multiple autoimmune side effects of immune checkpoint inhibitors in a patient with metastatic melanoma receiving pembrolizumab. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

From bench to bedside: the history and progress of CAR T cell therapy. [2023]

11. New Zealand 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. [2022]