CAR T-Cell Therapy for Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mehrdad Abedi, MD

Must not be taking: Immunosuppressants, Investigational drugs

Disqualifiers: Autoimmune diseases, Active CNS involvement, others

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

Compensation: Varies

Number of Visits: 31

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach called CAR T-cell therapy for diffuse large B-cell lymphoma that has returned or resisted previous treatments. Researchers aim to determine the optimal dose and assess potential benefits or side effects of combining chemotherapy drugs like fludarabine and cyclophosphamide, sometimes with rituximab, before introducing the CAR T-cells. CAR T-cells are modified immune cells designed to target and kill cancer cells. Individuals with diffuse large B-cell lymphoma that has relapsed or is resistant to other treatments, and who have not succeeded with at least two prior therapies, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there is a requirement for a 'washout period' (time without taking certain medications) of at least 2 weeks or 5 half-lives for prior cancer-directed therapy before starting the trial.

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

Studies have shown that CAR T-cell therapy is generally safe, with side effects that are usually manageable. Patients with relapsed or hard-to-treat large B-cell lymphoma who received this therapy often experienced significant and lasting improvements, which is a positive result.

The chemotherapy drugs used before CAR T-cell therapy—fludarabine, cyclophosphamide, and rituximab—have long been part of cancer treatment. They help the body accept the CAR T-cells by reducing the number of normal T-cells. Each drug can cause side effects, but patients often tolerate them well.

In summary, while these treatments can have side effects, research suggests they are generally manageable. Always consult your doctor to understand the risks and benefits specific to your health condition. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Chimeric Antigen Receptor (CAR) T-cell therapy is unique because it transforms a patient's own T-cells to specifically target and destroy cancer cells, especially in lymphoma. Unlike traditional treatments like chemotherapy or radiation, which can affect both healthy and cancerous cells, CAR T-cell therapy offers a targeted approach, reducing damage to healthy cells. Researchers are excited about this therapy because it harnesses the body's immune system for a precise attack, potentially leading to more effective and longer-lasting remissions. Additionally, the combination with drugs like rituximab, fludarabine, and cyclophosphamide may enhance its effectiveness by preparing the body and reducing the cancer burden before CAR T-cell infusion.

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

Research has shown that CAR T-cell therapy yields promising results for treating diffuse large B-cell lymphoma (DLBCL) that is difficult to treat or has recurred. Studies have found that this therapy can lead to long-term remission in some patients with blood cancers. The treatment modifies T-cells in the lab to enhance their ability to find and destroy cancer cells. This method is effective for patients whose cancer hasn't responded to other treatments. In this trial, participants will receive different combinations of CAR T-cell therapy with drugs such as rituximab, fludarabine, and cyclophosphamide to evaluate the effectiveness of these combinations. Overall, CAR T-cell therapy offers a promising option with a successful track record in similar conditions. ^{4 6 7 8 9}

Who Is on the Research Team?

Mehrdad Abedi, MD

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

Adults with relapsed or refractory diffuse large B-cell lymphoma who've had at least two prior therapies can join this trial. They must be in good health, able to take oral meds, and not use tobacco or drugs. Women of childbearing age and men must agree to effective contraception.

Inclusion Criteria

Platelets >= 100/mm^3

For females of reproductive potential: use of highly effective contraception (oral contraceptives, intrauterine device) during screening confirmed with serum pregnancy test, and agreement to use such a method during study participation and for an additional 4 weeks after the end of CD19 CAR T cell infusion

I have diffuse large B cell lymphoma that didn't fully respond to at least two treatments including an anthracycline and an anti-CD20 drug.

Exclusion Criteria

I have not had a fever in the 3 days before starting my immune system lowering therapy.

I have hepatitis but my PCR test for it is negative.

I had my own cells transplanted within 6 weeks or received a donor's cells within 3 months before planned CAR T cell therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive fludarabine and cyclophosphamide with or without rituximab to reduce normal T-cells and prepare for CAR T-cell infusion

5 days

Daily visits for chemotherapy administration

CAR T-cell Infusion

Participants receive CD19 CAR T cells intravenously to target and destroy cancer cells

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after CAR T-cell therapy

Up to 15 years

Follow-up at 30, 60, and 90 days, 6 and 12 months, then annually

What Are the Treatments Tested in This Trial?

Interventions

• Chimeric Antigen Receptor T-Cell Therapy
• Cyclophosphamide
• Fludarabine Phosphate
• Rituximab

Trial Overview The trial is testing the effectiveness of fludarabine and cyclophosphamide chemotherapy with or without rituximab before administering modified T-cells (CD19 CAR T-cell therapy) designed to target and kill lymphoma cells.

How Is the Trial Designed?

Group I: Dose level 6 (rituximab, fludarabine, cyclophosphamide, CAR T) Experimental Treatment 4 Interventions

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -1, and cyclophosphamide IV over 60 minutes on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0.

Group II: Dose level 5 (fludarabine, cyclophosphamide, CD19 CAR T) Experimental Treatment 3 Interventions

Patients receive fludarabine phosphate IV over 30 minutes daily on days -5 to -1 and cyclophosphamide IV over 60 minutes daily on days -5 and -4. Patients also receive CD19 CAR T cells IV on day 0.

Group III: Dose level 4 (rituximab, fludarabine, cyclophosphamide, CAR T) Experimental Treatment 4 Interventions

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on day -5. Patients also receive CD19 CAR T cells IV on day 0.

Group IV: Dose level 3 (fludarabine, cyclophosphamide, CD19 CAR T) Experimental Treatment 3 Interventions

Patients receive fludarabine phosphate IV over 30 minutes daily on days -3 to -5 and cyclophosphamide IV over 60 minutes daily on day -5. Patients also receive CD19 CAR T cells IV on day 0.

Group V: Dose level 2 (rituximab, fludarabine, cyclophosphamide, CAR T) Experimental Treatment 4 Interventions

Patients receive rituximab IV on day -5, fludarabine phosphate IV over 30 minutes daily on days -5 to -3, and cyclophosphamide IV over 60 minutes on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0.

Group VI: Dose level 1 (fludarabine, cyclophosphamide, CD19 CAR T) Experimental Treatment 3 Interventions

Patients receive fludarabine phosphate IV over 30 minutes daily and cyclophosphamide IV over 60 minutes daily on days -5 to -3. Patients also receive CD19 CAR T cells IV on day 0.

Chimeric Antigen Receptor T-Cell Therapy is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Tisagenlecleucel for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Axicabtagene ciloleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Tecartus for:

• Mantle cell lymphoma
• Acute lymphoblastic leukemia

Approved in United States as Tecartus for:

• Mantle cell lymphoma
• Acute lymphoblastic leukemia

Approved in European Union as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

Approved in United States as Brexucabtagene autoleucel for:

• Mantle cell lymphoma

Approved in European Union as Lisocabtagene maraleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in United States as Lisocabtagene maraleucel for:

• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in Canada as CAR T-cell therapy for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in Japan as CAR T-cell therapy for:

• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma

Who Is Running the Clinical Trial?

Mehrdad Abedi, MD

Lead Sponsor

Trials

4

Recruited

70+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

CAR T-cell therapy, particularly with anti-CD19 targeting, has shown significant effectiveness in treating aggressive B-cell non-Hodgkin's lymphoma (NHL), leading to long-term remissions in patients with diffuse large B-cell lymphoma (DLBCL) who have not responded to other treatments.

Two CAR T-cell products, axicabtagene ciloleucel and tisagenlecleucel, have been approved by the FDA for refractory DLBCL, while a third product, liso-cel, is showing promising results in ongoing trials, although potential side effects like cytokine-release syndrome and neurotoxicity are important considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Chavez, JC., Bachmeier, C., Kharfan-Dabaja, MA.[2020]

Recent phase 3 clinical trials have shown that CD19-directed CAR T cell therapies, specifically axicabtagene ciloleucel and lisocabtagene maraleucel, significantly improve outcomes in patients with relapsed/refractory aggressive diffuse large B cell lymphoma compared to standard treatments, while tisagenlecleucel did not demonstrate a similar benefit.

The FDA has approved axicabtagene ciloleucel and lisocabtagene maraleucel for use in patients whose lymphoma is refractory to first-line chemoimmunotherapy or who relapse within 12 months, marking a significant advancement in treatment options for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of CD19 Chimeric Antigen Receptor T Cells in Second-Line Large B Cell Lymphoma: Lessons from Phase 3 Trials. An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Perales, MA., Anderson, LD., Jain, T., et al.[2023]

In a pivotal phase 2 study involving 93 adult patients with relapsed or refractory diffuse large B-cell lymphoma, CAR T-cell therapy with tisagenlecleucel achieved a best overall response rate of 52%, with 40% of patients experiencing complete responses.

The treatment demonstrated durable responses, with a 12-month relapse-free survival rate of 65%, and no deaths were attributed to the therapy itself, although some patients experienced significant adverse events like cytokine release syndrome and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Schuster, SJ., Bishop, MR., Tam, CS., et al.[2019]

CAR-T cell therapies, specifically axicabtagene ciloleucel and tisagenlecleucel, have significantly improved outcomes for patients with relapsed or refractory aggressive B-cell lymphomas, with approvals based on pivotal trials demonstrating their efficacy after multiple prior treatments.

Despite their similar CAR technologies, differences in manufacturing and clinical trial designs exist between these therapies, highlighting the need for ongoing monitoring of patient responses and potential long-term side effects in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. Westin, JR., Kersten, MJ., Salles, G., et al.[2022]

Anti-CD19-directed CAR T cell therapy has shown significant efficacy in treating relapsed or refractory B-cell malignancies, leading to the approval of tisagenlecleucel (Kymriah) for B-ALL in 2018 and for aggressive B-cell lymphoma shortly thereafter.

The review highlights ongoing research into resistance mechanisms and the exploration of new target antigens, indicating a continued effort to improve treatment outcomes for patients with CD19 positive B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. Balke-Want, H., Borchmann, P.[2021]

In a study of 72 adult patients with relapsed or refractory non-Hodgkin lymphoma treated with tisagenlecleucel, 94.4% received the therapy in an outpatient setting, demonstrating that this approach is both safe and feasible.

The overall response rate was 43%, with a complete response in 34.7% of patients, and serious adverse events like grade 3-4 cytokine release syndrome were not observed, indicating a manageable safety profile for outpatient CAR T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting. Nasta, SD., Hughes, ME., Namoglu, EC., et al.[2022]

CAR T-cell therapy targeting CD19 has transformed the treatment landscape for relapsed or refractory B-cell lymphomas, leading to rapid FDA approval for multiple lymphoma subtypes due to high response rates and durability.

Three second-generation anti-CD19 CAR T-cell products have been approved for use in aggressive non-Hodgkin's lymphoma, and ongoing research is focused on understanding treatment failures and improving outcomes for patients who do not respond to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphoma. Denlinger, N., Bond, D., Jaglowski, S.[2022]

Cytokine release syndrome (CRS) is the most common adverse reaction reported after CAR-T therapy, with significantly higher reports for axicabtagene ciloleucel compared to tisagenlecleucel, indicating a need for careful monitoring of this side effect.

The study analyzed 1426 reports of adverse drug reactions from real clinical settings, supporting the overall safety profile of CAR-T therapies while confirming CRS as a major concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. Bonaldo, G., Montanaro, N., AlbertoVaccheri, ., et al.[2021]

In a study of 258 patients receiving CAR T-cell therapy for large B-cell lymphoma, 72% experienced severe neutropenia, with a median duration of 9 days, highlighting the significant risk of hematotoxicity associated with this treatment.

The CAR-HEMATOTOX model was developed to predict the duration of severe neutropenia based on baseline markers like platelet count and inflammation, showing high accuracy (AUC 0.89) and helping to identify patients at greater risk for prolonged cytopenia, which can guide management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Rejeski, K., Perez, A., Sesques, P., et al.[2022]

CAR T-cell therapies have significantly changed treatment options for patients with relapsed or refractory aggressive B-cell lymphomas, with three products currently approved or nearing approval.

Selecting the right CAR T-cell product for a patient involves careful consideration of various factors, including the patient's age, health status, previous treatments, and the specific characteristics of each CAR T-cell product.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient selection for chimeric antigen receptor (CAR) T-cell therapy for aggressive B-cell non-Hodgkin lymphomas. Johnson, PC., Abramson, JS.[2021]

The three CAR-T cell therapies (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) show promising efficacy in treating large B cell lymphoma, with overall response rates of nearly 70% and complete response rates exceeding 50% across 33 studies involving 2,172 patients.

However, axicabtagene ciloleucel and tisagenlecleucel are associated with significant risks of severe neurotoxicity and life-threatening cytokine release syndrome, necessitating careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of CAR-T Cell Products Axicabtagene Ciloleucel, Tisagenlecleucel, and Lisocabtagene Maraleucel for the Treatment of Hematologic Malignancies: A Systematic Review and Meta-Analysis. Meng, J., Wu, X., Sun, Z., et al.[2022]

Citations

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Chimeric Antigen Receptor (CAR) T-cell Therapy in the ... CAR T-cell therapy has shown very promising results in the treatment of refractory or relapsed diffuse large B-cell lymphoma (DLBCL).

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Real-World Outcomes with Chimeric Antigen Receptor T ... Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL.

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Long-term outcomes following CAR T cell therapy The data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term ...

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Chimeric antigen receptor (CAR) T-cell therapy The therapy has resulted in long-term remissions for some patients with certain types of blood cancer. FDA-approved treatments. The following FDA-approved ...

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Health and Economic Impact of Vein-to-Vein Time in CAR ... These findings suggest that reduced V2VT was associated with improved clinical and economic outcomes, and highlight the importance of short V2VT ...

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Adverse Events After CAR T-Cell Therapy in B-Cell Non- ... Chimeric antigen receptor (CAR) T-cell therapy has improved the outcome of patients with relapsed or refractory aggressive large B-cell lymphoma ...

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Analysis of real-world (RW) AE reporting from the FDA ... Background: CAR T cell therapies have emerged as effective treatment options with deep and durable responses in patients (pt) with DLBCL.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37890589/

Real-World Outcomes with Chimeric Antigen Receptor T ... Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL.

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37760639/

Outcomes of Chimeric Antigen Receptor (CAR) T-Cell ... We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received ...