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

Trial Summary

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.

What data supports the effectiveness of the treatment CAR T-Cell Therapy for Lymphoma?

CAR T-cell therapies, including axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel, have shown significant improvements in patients with relapsed or refractory aggressive B-cell lymphomas, as demonstrated in clinical trials like ZUMA-7 and TRANSFORM. These therapies have been approved by the FDA due to their ability to provide unprecedented response rates and durability of response in high-risk patients. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for humans?

CAR T-cell therapies, like axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating certain lymphomas and have shown good results, but they can cause side effects like cytokine-release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These therapies are generally considered safe, but monitoring for long-term side effects is important. ^{2 5 6 7 8}

How is CAR T-cell therapy different from other treatments for lymphoma?

CAR T-cell therapy is unique because it uses genetically modified T-cells (a type of immune cell) to specifically target and destroy cancerous B-cells in lymphoma, offering a new option for patients who have not responded to traditional treatments. This therapy has shown promising results in achieving long-term remissions, even in aggressive cases where other treatments have failed. ^{5 7 9 10 11}

What is the purpose of this trial?

This phase I trial evaluates the best dose, possible benefits and/or side effects of fludarabine and cyclophosphamide with or without rituximab before CD19 chimeric antigen receptor T cells in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or has not responded to previous treatment (refractory). T-cells are a normal part of the immune system. To make the T-cell medication, T-cells are taken from the blood and altered in a laboratory. They are then returned to the body. The altered T-cells will latch on to a specific part of the cancer cells and hopefully kill them. Once the T-cells have been altered in the laboratory, they are called "CAR T-cells." CAR is short for "chimeric antigen receptors." These are structures on the surface of cells that allow the altered T-Cells to find and destroy the cancer cells. Another part of the T-Cell medication is called "CD19." This part is called a "biomarker." Biomarkers help doctors determine whether a cancer is getting worse and whether medications are working to stop it. The chemotherapy drugs that are given before the T-Cell therapy are cyclophosphamide, fludarabine and rituximab. Rituximab is an immunotherapy drug. These chemotherapy drugs will reduce the number of normal (unaltered) T-Cells in the body to make room for the altered T-cells to kill the cancer cells. Giving fludarabine and cyclophosphamide with or without rituximab before CD19 CAR T cell therapy may help improve response to CD19 CAR T cell therapy in patients with diffuse large B-cell lymphoma.

Research Team

Mehrdad Abedi, MD

Principal Investigator

University of California, Davis

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. United States 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. [2022]

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

CAR T-cell therapy for B-cell lymphoma. [2022]

4. United States 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. [2023]

5. Switzerland 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. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice. [2021]

7. England pubmed.ncbi.nlm.nih.gov

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. [2020]

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

CAR-HEMATOTOX: a model for CAR T-cell-related hematologic toxicity in relapsed/refractory large B-cell lymphoma. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. [2021]

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

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting. [2022]

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

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. [2019]