Radiation + CAR-T Therapy for Non-Hodgkin's Lymphoma

Overseen By Ruthie Chae

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Systemic steroids

Disqualifiers: Cardiac disease, HIV, Hepatitis B, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of radiation therapy and CAR-T cell therapy (Chimeric Antigen Receptor T-Cell Therapy) to determine its effectiveness in treating large B-cell lymphoma, a type of non-Hodgkin's lymphoma. The focus is on advanced cases with large tumors. The trial aims to assess the safety and effectiveness of administering radiation before CAR-T therapy. It seeks participants with diffuse large B-cell lymphoma and at least one tumor measuring 5 cm or larger. Participants must be eligible for radiation and have no active central nervous system involvement of lymphoma. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in lymphoma treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on chronic systemic steroids or immunosuppressant medications, unless they are stopped at least 5 days before a specific procedure called leukapheresis.

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

A previous study showed that CAR T-cell therapy is a strong option for treating certain blood cancers, such as non-Hodgkin's lymphoma. Many patients experienced positive results from this treatment. However, some people reported side effects, including fever, low blood pressure, and neurological symptoms like confusion or headaches. Overall, studies have shown that most people handle it well.

Research indicates that using bridging radiation therapy before CAR T-cell therapy has been safe and effective for non-Hodgkin's lymphoma. A large review found that only 2% of patients experienced severe side effects from the radiation, suggesting that most people tolerate it well.

In summary, while some risks exist, studies indicate that the treatments in this trial are generally safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for Non-Hodgkin's Lymphoma, like chemotherapy and monoclonal antibodies, work by broadly attacking cancer cells. But this new treatment approach combines CAR-T therapy with radiation, offering a unique one-two punch. CAR-T therapy involves reprogramming a patient's own T-cells to specifically target and kill cancer cells, while the radiation helps to shrink tumors and potentially makes the CAR-T cells even more effective. Researchers are excited because this combination could lead to a more targeted and potent attack on lymphoma cells, potentially improving outcomes for patients.

What evidence suggests that this trial's treatments could be effective for Non-Hodgkin's Lymphoma?

Research has shown that CAR T-cell therapy effectively treats certain blood cancers, such as B-cell and plasma cell cancers. Many patients have experienced long periods of remission after treatment. The CD19 CAR T-cells used in this therapy have significantly reduced cancer cells and helped prevent recurrence. In this trial, participants will receive a combination of radiation therapy and CAR T-cell infusion. Studies suggest that adding a type of radiation treatment before CAR T-cell therapy might improve outcomes for patients with non-Hodgkin's lymphoma. This radiation can target large cancer areas, potentially enhancing the effectiveness of CAR T-cells. Overall, combining these treatments appears promising for managing difficult cases of lymphoma. ^{1 6 7 8 9}

Who Is on the Research Team?

Michael Jain, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with large B-cell lymphoma who have a lesion at least 5 cm big and are fit enough to undergo radiation therapy. They must not be pregnant, agree to use contraception, and cannot have HIV or active hepatitis. Those previously treated with CAR T-cell therapy or having heart issues, uncontrolled infections, or requiring steroids/immunosuppressants can't join.

Inclusion Criteria

Women of child-bearing potential and men must commit to using effective contraception (hormonal or barrier method, abstinence) pre-enrolment in the trial and until completion for the safety of unborn human fetuses whose effects are not known.

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

My blood and organs are working well.

Exclusion Criteria

I haven't taken any experimental drugs in the last 4 weeks.

My heart rhythm problem hasn't been stable on medication for the last 2 weeks.

I have previously undergone CAR T-cell therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo Comprehensive Ablative Bridging Irradiation (CABI) to all pretreatment lesions

2-3 weeks

Chemotherapy

Participants undergo lymphodepleting chemotherapy period (Days -5, -4, -3) followed by axi-cel infusion (Day 0)

1 week

Follow-up

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

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Chimeric Antigen Receptor T-Cell Therapy
• Comprehensive Ablative Bridging Irradiation (CABI)

Trial Overview The study tests the safety and effectiveness of comprehensive bridging radiation therapy before CD19 CAR T-cell treatment in patients with bulky disease. It's an open-label phase 2 trial where all participants receive both treatments sequentially.

How Is the Trial Designed?

Group I: Radiation Therapy and CAR T-Cell Infusion Experimental Treatment 2 Interventions

Following T-cell apheresis for CD19 CAR T-cell therapy, eligible enrolled study participants patients will undergo Comprehensive Ablative Bridging Irradiation (CABI) to all pretreatments lesions that are able to be feasibly and safely treated by the treating radiation oncologist. Upon completion of bridging radiotherapy, patients will undergo lymphodepleting chemotherapy period (Days -5, -4, -3) followed by axi-cel infusion (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?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Kite, A Gilead Company

Industry Sponsor

Trials

45

Recruited

4,300+

Published Research Related to This Trial

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]

Tisagenlecleucel, an anti-CD19 CAR-T cell therapy, has been approved for treating pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), showing significant long-term effectiveness and overall survival benefits.

While CAR-T cell therapy can lead to serious adverse events like cytokine release syndrome and neurological toxicities, these effects are manageable with proper medical training and protocols, highlighting the importance of specialized care in administering this innovative treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T Cell Therapy: Practical Considerations for Implementation in Europe. Buechner, J., Kersten, MJ., Fuchs, M., et al.[2020]

The analysis of data from the FDA's Adverse Event Reporting System revealed that the CAR-T product Tisagenlecleucel had a notably high rate of severe outcomes, with 53.24% of cases resulting in death and 13.39% being life-threatening.

Different CAR-T therapies, particularly Axicabtagene ciloleucel and Tisagenlecleucel, showed varying frequencies and types of cardiac events, highlighting the need for careful monitoring of cardiac risks associated with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study. Zhai, Y., Hu, F., Zhu, B., et al.[2023]

CD19-directed CAR T-cell therapy, particularly axicabtagene ciloleucel, is highly effective for treating relapsed/refractory large B-cell lymphoma, but it comes with significant risks of treatment-emergent toxicities such as cytokine release syndrome and neurotoxicity.

Understanding the safety profile and potential complications of CAR T-cell therapy is crucial for selecting appropriate patients and implementing preventative measures, which can enhance the overall safety and effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. Nath, K., Wudhikarn, K., Alarcon Tomas, A., et al.[2023]

Chimeric antigen receptor (CAR) T cell therapies, specifically axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating large B-cell lymphomas after two prior therapies, showing durable remissions in 30% to 40% of patients.

While these therapies are effective, they can cause serious side effects like cytokine release syndrome and neurotoxicity, necessitating treatment in specialized medical centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Chow, VA., Shadman, M., Gopal, AK.[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]

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]

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]

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