Bridging Radiation Therapy for Lymphoma

Overseen By Maribeth A Hohenstein, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Nebraska

Must not be taking: High dose methotrexate

Disqualifiers: Primary CNS lymphoma, Secondary active malignancy, others

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

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

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if administering radiation therapy before CAR T-cell treatment is safe and feasible for individuals with B-cell lymphoma that has not improved or has worsened after treatment. The focus is on using radiation to prepare the body for Liso-cel, a type of CAR T-cell therapy. The trial seeks participants with specific types of B-cell lymphoma, such as diffuse large B-cell lymphoma, who have experienced difficulties with previous treatments. Participants should have a disease site that can safely receive radiation. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use lymphoma-directed therapy within 14 days of T-cell pheresis.

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

Research has shown that liso-cel, a treatment for certain types of lymphoma, is generally safe. Most patients tolerate it well, though some may experience side effects like cytokine release syndrome (CRS) and nerve-related issues. These side effects are known and usually managed effectively.

Studies indicate that radiation therapy used before CAR T-cell treatments like liso-cel does not increase side effects. It is considered safe and practical, with most patients completing the treatment without new safety concerns.

Overall, previous research has demonstrated that both radiation and liso-cel treatments are safe and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for lymphoma, which typically involve chemotherapy and radiation, Liso-cel is a type of CAR T-cell therapy that offers a more targeted approach. CAR T-cell therapy works by modifying a patient's own immune cells to better recognize and attack cancer cells. Researchers are excited about Liso-cel because it has the potential to provide a more personalized treatment with fewer side effects compared to conventional chemotherapy. Additionally, its ability to be combined with radiation therapy in a structured way could enhance its effectiveness, offering hope for more robust and lasting responses in lymphoma patients.

What evidence suggests that bridging radiation therapy and Liso-cel could be effective for B-cell lymphoma?

Research has shown that liso-cel, the primary treatment in this trial, effectively treats B-cell lymphoma, especially when other treatments have failed. In one study, 95.5% of patients with marginal zone lymphoma responded well to liso-cel. Another study found that 84% of patients had a positive response, with 68% experiencing a complete response, meaning their cancer was no longer detectable.

Participants in this trial will receive bridging radiation therapy before CAR T-cell treatments like liso-cel. Using radiation therapy in this manner also appears promising. Specifically, one study found that 82.4% of patients responded well after combining these treatments. This suggests that using radiation therapy before CAR T-cell treatment can be a helpful strategy for patients with difficult-to-treat lymphoma. ^{3 4 6 7 8}

Who Is on the Research Team?

Christopher R D'Angelo, MD

Principal Investigator

University of Nebraska

Are You a Good Fit for This Trial?

This trial is for adults aged 19 or older with B-cell lymphoma that has returned or worsened despite treatment. They should be able to perform daily activities (ECOG status 0-2) and have a type of lymphoma eligible for liso-cel infusion, with at least one tumor site safe for radiation. Participants must have good organ function and agree to the study's procedures.

Inclusion Criteria

I am 19 years old or older.

I am able to get out of my bed or chair and move around.

My lymphoma has returned or worsened and fits the type for a specific treatment.

Exclusion Criteria

Uncontrolled medical, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol, as determined by investigator

I need to take high dose methotrexate.

Pregnant or nursing women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive low-dose radiation therapy as bridging treatment before CAR T-cell therapy

Up to 90 days

2 visits (in-person)

CAR T-cell Infusion

Participants receive chimeric antigen receptor (CAR) T-cell infusion following radiation therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 270 days

Multiple visits (in-person and virtual)

What Are the Treatments Tested in This Trial?

Interventions

• Bridging radiation therapy
• Liso-cel
• Post-infusion radiation

Trial Overview

The trial is testing if low dose radiation can be used as a 'bridge' before CAR T-cell therapy in patients with certain types of B-cell lymphoma. It aims to determine the feasibility and safety of this approach prior to administering the standard CAR T-cell treatment.

How Is the Trial Designed?

Group I: Single arm Experimental Treatment 3 Interventions

Subjects will receive 4 gray (Gy) radiation in 2 fractions in the bridging period following lymphocyte pheresis, prior to lymphodepleting chemotherapy and chimeric antigen receptor (CAR) T-cell infusion. Post CAR T-cell infusion radiation therapy will be allowed as determined by study investigator but prespecified at time of radiation oncology consultation.

Liso-cel is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Breyanzi for:

• Relapsed or refractory large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Breyanzi for:

• Relapsed or refractory diffuse large B-cell lymphoma
• Follicular lymphoma

Approved in Japan as Breyanzi for:

• Relapsed or refractory large B-cell lymphoma

Approved in Canada as Breyanzi for:

• Relapsed or refractory large B-cell lymphoma

Who Is Running the Clinical Trial?

University of Nebraska

Lead Sponsor

Trials

563

Recruited

1,147,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In a study involving 344 patients with relapsed or refractory large B-cell lymphomas, lisocabtagene maraleucel (liso-cel) demonstrated a high objective response rate of 73%, with 53% achieving a complete response, indicating its efficacy as a treatment option.

The safety profile of liso-cel was acceptable, with a low incidence of severe cytokine release syndrome (2%) and neurological events (10%), suggesting it can be safely administered to patients with various high-risk features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Abramson, JS., Palomba, ML., Gordon, LI., et al.[2021]

Lisocabtagene maraleucel (liso-cel) is an effective CAR T cell therapy for relapsed or refractory large B cell lymphoma, showing a 73% objective response rate and a 53% complete remission rate in a study of 344 patients.

The treatment demonstrated a 12-month overall survival rate of 58% for all patients and 86% for those who achieved complete remission, although it was associated with adverse events such as cytokine release syndrome (42%) and neurological issues (30%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene Maraleucel in Relapsed or Refractory Diffuse Large B Cell Lymphoma: What is the Evidence? Kharfan-Dabaja, MA., Yassine, F., Moustafa, MA., et al.[2023]

Lisocabtagene maraleucel (liso-cel) is an FDA-approved CAR T-cell therapy specifically for treating relapsed/refractory large B-cell lymphoma, with its approval based on the successful TRANSCEND trial.

The review highlights the unique structure and manufacturing process of liso-cel, as well as its efficacy and safety profile demonstrated in landmark trials, including its evaluation in the second-line treatment setting through the TRANSFORM and PILOT studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma. St-Pierre, F., Gordon, LI.[2023]

Lisocabtagene maraleucel (Breyanzi) has been approved by the FDA for treating adults with large B-cell lymphoma who have relapsed or are refractory after initial treatment, highlighting its efficacy in a challenging patient population.

Due to the risk of serious side effects like cytokine release syndrome and neurological toxicities, patients must be closely monitored for at least seven days post-infusion, emphasizing the importance of safety in its administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approval for Drug Treating Large B-Cell Lymphoma. Aschenbrenner, DS.[2023]

In a phase 3 study involving 184 patients with primary refractory or early relapsed large B-cell lymphoma (LBCL), lisocabtagene maraleucel (liso-cel) significantly improved median event-free survival to 10.1 months compared to 2.3 months for standard care, indicating its efficacy as a second-line treatment.

The safety profile of liso-cel was manageable, with no new safety concerns identified; serious adverse events were similar between liso-cel and standard care, and there were no treatment-related deaths in the liso-cel group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Kamdar, M., Solomon, SR., Arnason, J., et al.[2022]

Topotecan (TPT) combined with radiation therapy showed a therapeutic gain in treating small cell lung carcinoma and glioblastoma multiforme in mouse models, with efficacy being dose-dependent and varying between tumor types.

The combination of TPT and radiation did not significantly alter tumor oxygenation or skin radiation reactions, indicating that TPT can enhance treatment effectiveness without causing substantial adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan selectively enhances the radioresponse of human small-cell lung carcinoma and glioblastoma multiforme xenografts in nude mice. Chastagner, P., Kozin, SV., Taghian, A.[2019]

The study determined that the maximum tolerated dose of intravenous topotecan (0.5 mg/m²) combined with cisplatin (30 mg/m²) during pelvic radiation therapy is tolerable for women with locally advanced cervical cancer, with manageable side effects.

Dose-limiting toxicities were observed at higher doses, including severe nausea, vomiting, and neutropenia, leading to a necessary adjustment in the treatment regimen to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: a gynecologic oncology group study. Rose, PG., Sill, MW., McMeekin, DS., et al.[2021]

Combining chemotherapy with radiation therapy has shown significant clinical advancements in cancer treatment, particularly through the use of systemic therapies that can enhance tumor control (radiosensitization) and reduce damage to healthy tissues (radioprotection).

Recent early-phase clinical trials have focused on identifying effective combinations of systemic agents with radiation, suggesting that using surrogate endpoints, like active drug metabolites in tumors, could help streamline the search for optimal treatment schedules, although more robust Phase III trials are still needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New and emerging radiosensitizers and radioprotectors. Spalding, AC., Lawrence, TS.[2007]

In a phase 2 trial involving 61 patients with relapsed or refractory large B-cell lymphoma, lisocabtagene maraleucel demonstrated a high overall response rate of 80%, indicating its efficacy as a second-line treatment for patients not intended for stem-cell transplantation.

The treatment was generally safe, with no treatment-related deaths reported; however, common serious side effects included neutropenia and cytokine release syndrome, which occurred in 38% of patients, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Sehgal, A., Hoda, D., Riedell, PA., et al.[2022]

Radiation therapy is a key treatment for over 60% of cancer patients, but its effectiveness can be modestly improved with cytotoxic chemotherapy, highlighting the need for better combination therapies.

Current clinical trials combining targeted agents or immunotherapies with radiation therapy have largely failed, indicating a need for more rigorous preclinical testing to identify safe and effective drug combinations for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations. Lin, SH., Willers, H., Krishnan, S., et al.[2022]

In a study of 214 cancer patients undergoing radiotherapy, 72% were prescribed non-anticancer treatments (NACTs), with a median of 5 different NACTs per patient, highlighting the common use of these medications alongside radiation therapy.

Only a small fraction (0.9%) of the 833 different NACTs reported were identified as potential modifiers of cancer pathways, indicating a need for more research and clinical trials to explore the interactions between NACTs and radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing drug/radiation interaction through daily routine practice: Leverage medical and methodological point of view (MORSE 02-17 study). Vallard, A., Rancoule, C., Espenel, S., et al.[2019]

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This metaanalysis found that BRT use prior to CART19, whether as a standalone approach or in combination with systemic therapy, does not increase toxicity.

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