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

Overseen By Marissa Folsom

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

Trial Summary

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.

What data supports the effectiveness of the treatment Radiation + CAR-T Therapy for Non-Hodgkin's Lymphoma?

CAR-T cell therapies, such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel, have shown to be effective for patients with relapsed or refractory aggressive B-cell lymphomas, with durable remissions seen in 30% to 40% of patients. These therapies are approved for large B-cell lymphomas and have transformed treatment options for these conditions. ^{1 2 3 4 5}

Is CAR-T therapy safe for humans?

CAR-T cell therapies, like axicabtagene ciloleucel and tisagenlecleucel, have been approved for certain types of lymphoma and have shown good results, but they can cause side effects such as cytokine release syndrome (a severe immune reaction), neurological issues, and heart problems. These side effects are manageable with proper medical care, but they highlight the importance of monitoring and managing patients carefully during treatment. ^{1 3 6 7 8}

What makes the treatment Radiation + CAR-T Therapy for Non-Hodgkin's Lymphoma unique?

Radiation + CAR-T Therapy is unique because it combines radiation with CAR-T cell therapy, which uses modified immune cells to target cancer cells. This approach is novel as it leverages the precision of CAR-T cells, which have shown promise in treating relapsed or refractory aggressive B-cell lymphomas, and combines it with radiation to potentially enhance treatment effectiveness. ^{1 2 3 4 5}

What is the purpose of this trial?

This is a phase 2, single-arm, open-label study to evaluate the safety and efficacy of comprehensive bridging radiation therapy prior to CD19 CAR T-cell therapy for large B-cell lymphoma patients with bulky disease, defined as any lesion ≥5 cm.

Research Team

Michael Jain, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. 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]

2. 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]

3. 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]

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

Safety evaluation of axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma. [2023]

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

Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. [2022]

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

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

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

Chimeric Antigen Receptor-T Cell Therapy: Practical Considerations for Implementation in Europe. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study. [2023]