CAR T-Cell Therapy for Central Nervous System Lymphoma

Not currently recruiting at 1 trial location

Overseen By Caron Jacobson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Immunostimulatory agents, CAR-T therapy

Disqualifiers: Primary vitreoretinal lymphoma, Brain stem lesions, Leptomeningeal disease, Cardiac disease, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called axicabtagene ciloleucel (axi-cel) to determine its safety and effectiveness for individuals with certain types of central nervous system (CNS) lymphoma that have recurred or resisted other treatments. Axi-cel, a type of CAR T-cell therapy, uses modified immune cells to target and kill cancer cells. Participants will also receive fludarabine and cyclophosphamide to enhance the therapy's effectiveness. The trial seeks individuals with aggressive B cell lymphoma affecting the brain, particularly if previous treatments have failed. Participants should have active CNS lymphoma visible on an MRI scan. 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 requires that at least 2 weeks or 5 half-lives, whichever is shorter, must have passed since any prior systemic cancer therapy before joining. Additionally, you cannot have taken systemic immunostimulatory agents within 6 weeks or 5 half-lives before the first dose of the study drug.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that axicabtagene ciloleucel (axi-cel) is generally safe for treating certain types of lymphoma, including those affecting the central nervous system. Many patients can use axi-cel without experiencing severe side effects.

In another study, most patients managed the treatment well, although some experienced side effects, including neurological symptoms, which researchers aim to understand better. Axi-cel is already approved for other types of lymphoma, indicating that health authorities consider it safe to a certain extent.

Fludarabine and cyclophosphamide are used with axi-cel to enhance its effectiveness. These drugs are usually well-tolerated but can lower blood cell counts, potentially affecting the body's ability to fight infections or stop bleeding.

Overall, while any treatment carries risks, studies have shown that many people handle axi-cel and the accompanying drugs without serious problems. It's always best to discuss with healthcare providers what these findings might mean for a specific situation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike traditional treatments for central nervous system lymphoma, which often involve chemotherapy and radiation, axicabtagene ciloleucel represents an innovative approach by harnessing the body's own immune system. This treatment is a type of CAR T-cell therapy, which works by modifying a patient's T-cells in the lab so they can better identify and attack cancer cells. Researchers are excited about axicabtagene ciloleucel because it offers a more targeted attack on the cancer, potentially leading to more effective outcomes and fewer side effects compared to the broader impacts of conventional therapies. This targeted mechanism could be particularly promising for a condition as challenging as central nervous system lymphoma.

What evidence suggests that axicabtagene ciloleucel could be an effective treatment for CNS lymphoma?

Research has shown that axicabtagene ciloleucel (axi-cel), the treatment under study in this trial, may help treat certain aggressive lymphomas. Studies have found that axi-cel can improve survival rates in patients with large B-cell lymphoma, similar to the cancer being studied. Real-world evidence indicates that many patients benefit significantly from this therapy. Notably, patients with cancer affecting the central nervous system have responded well to axi-cel, highlighting its potential effectiveness. In this trial, participants will receive axi-cel in combination with fludarabine and cyclophosphamide, which may enhance the immune system's ability to fight cancer. Overall, early findings suggest that axi-cel could be a strong option for treating central nervous system lymphomas. ^{1 3 5 6 7}

Who Is on the Research Team?

Caron Jacobson

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults over 18 with relapsed/refractory central nervous system (CNS) lymphoma or systemic lymphoma with CNS involvement, who've had at least one prior treatment. They must have adequate organ function, no severe infections, and not be pregnant or breastfeeding. Excluded are those with certain heart conditions, active infections requiring IV treatment, history of other cancers within 3 years (except some skin cancers), and those unable to undergo MRI.

Inclusion Criteria

My brain lymphoma has returned or didn't respond after treatment.

My lymphoma is aggressive and has come back or didn't respond to treatment.

My lymphoma has returned after treatment including an anti-CD20 drug and an anthracycline.

Exclusion Criteria

I have lymphoma in my eye but no brain disease, and haven't had systemic therapy.

I have a history of serious brain or nerve conditions.

I have a lesion in my brain stem.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Pre-treatment

Participants undergo leukapheresis and assessment for Ommaya reservoir placement prior to receiving axi-cel

1 week

1 visit (in-person)

Treatment

Participants receive fludarabine and cyclophosphamide from Day -5 to Day -3, admitted to hospital on Day -1, and receive axi-cel on Day 0

1 week

Hospital stay from Day -1 to at least Day 7

Initial Follow-up

Post-treatment follow-up occurs on Day 14 and Day 28 of Cycle 1

4 weeks

2 visits (in-person)

Extended Follow-up

Monthly follow-up visits in Cycles 2, 3, 6, 9, 12, 15, 18, 21, 24, then yearly after Cycle 24

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Axicabtagene Ciloleucel

Trial Overview The trial is testing axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy targeting CD19 in patients with specific types of CNS lymphomas that have returned after treatment. It includes pre-treatment drugs cyclophosphamide and fludarabine to enhance the effectiveness of axi-cel.

How Is the Trial Designed?

Group I: Fludarabine + Cyclophosphamide + Axicabtagene Ciloleucel Experimental Treatment 3 Interventions

Prior to receiving axi-cel, participants will undergo leukapheresis and the need for a Ommaya reservoir placement will be assessed and administered. Day -5 to Day -3 of 28 day study cycle Fludarabine and cyclophosphamide; Day -1 admitted to hospital, receive axi-cel on day 0; Till at least cycle day 7 hospital monitoring; post treatment follow up will occur on day 14 and day 28 of cycle 1, monthly in cycles 2, 3, 6, 9,12,15,18,21,24, then yearly after cycle 24.

Axicabtagene Ciloleucel is already approved in United States, European Union for the following indications:

Approved in United States as Yescarta for:

• Large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy
• Relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy
• Relapsed or refractory follicular lymphoma after two or more lines of systemic therapy

Approved in European Union as Yescarta for:

• Diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy
• Relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma, after two or more lines of systemic therapy
• Relapsed or refractory follicular lymphoma after three or more lines of systemic therapy

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Kite, A Gilead Company

Industry Sponsor

Trials

45

Recruited

4,300+

Published Research Related to This Trial

Axicabtagene ciloleucel and tisagenlecleucel are FDA-approved CAR T cell therapies specifically designed to target CD19 in patients with relapsed or refractory aggressive B cell non-Hodgkin lymphoma, marking a significant advancement in cellular immunotherapy.

Despite their transformative potential, there are ongoing concerns about the appropriate use and potential short- and long-term toxicities of these therapies, prompting expert consensus to guide clinicians in their application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy. Jain, T., Bar, M., Kansagra, AJ., et al.[2020]

In a phase 2 trial involving 111 patients with refractory large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high objective response rate of 82%, with 54% achieving a complete response, indicating its efficacy as a treatment option.

The treatment was associated with significant adverse events, including neutropenia in 78% of patients and neurologic events in 28%, highlighting the need for careful monitoring of safety during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. Neelapu, SS., Locke, FL., Bartlett, NL., et al.[2023]

Intracerebroventricular (ICV) delivery of CD19-targeted CAR T cells was found to completely and durably eliminate both central nervous system (CNS) and systemic lymphoma in a mouse model, while intravenous (IV) delivery did not achieve the same results.

The enhanced efficacy of ICV-delivered CAR T cells is attributed to their conditioning by cerebrospinal fluid, which improves their anti-lymphoma activity and memory function, suggesting a promising new treatment strategy for B-cell malignancies with CNS involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma. Wang, X., Huynh, C., Urak, R., et al.[2022]

In a study of 8 patients with secondary CNS lymphoma treated with CAR T cells targeting CD19, no patients experienced severe neurotoxicity, indicating a favorable safety profile for this therapy in this specific population.

Despite the exclusion of CNS involvement in earlier trials, the CAR T cells showed signs of expansion and activity within the CNS, suggesting potential efficacy for treating CNS lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Frigault, MJ., Dietrich, J., Martinez-Lage, M., et al.[2022]

In a study of 75 patients with large B-cell lymphoma receiving CAR T-cell therapy, high pretreatment levels of the cytokine IL6 were linked to severe immune-mediated toxicities like cytokine release syndrome (CRS) and neurotoxicity (NT).

The research also found that certain gene expressions in tumor biopsies indicated a proinflammatory tumor microenvironment, which may increase the risk of toxicity, suggesting that personalized management strategies could help mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel. Faramand, R., Jain, M., Staedtke, V., et al.[2021]

Axicabtagene ciloleucel (axi-cel) is an effective CAR T-cell therapy targeting CD19, showing high response rates and a manageable safety profile in patients with relapsed or refractory B-cell malignancies, particularly after two or more lines of prior treatment.

Axi-cel is FDA-approved for adult patients with specific types of B-cell lymphomas, including diffuse large B-cell lymphoma, and is currently being studied for its efficacy in other B-cell malignancies in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel for the treatment of relapsed/refractory B-cell non-Hodgkin's lymphomas. Sharma, P., King, GT., Shinde, SS., et al.[2018]

Axicabtagene ciloleucel (axi-cel) demonstrated impressive efficacy in treating relapsed/refractory large B-cell lymphoma, with overall and complete response rates of 83% and 58%, respectively, in the pivotal ZUMA-1 trial with a median follow-up of 27.1 months.

While axi-cel shows promise, it is associated with significant toxicities, including cytokine release syndrome (CRS) in 7% to 14% of patients and immune effector cell-associated neurotoxicity syndrome (ICANS) in 31% to 55%, highlighting the need for careful patient management and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma. Halford, Z., Anderson, MK., Bennett, LL.[2021]

Axicabtagene ciloleucel (axi-cel) is an FDA-approved CAR T-cell therapy specifically designed to target CD19, showing promise in treating relapsed or refractory aggressive non-Hodgkin's lymphomas, including diffuse large B-cell lymphoma.

While axi-cel has demonstrated significant efficacy in clinical trials (ZUMA-1 Phase I and II), it is associated with potential toxicities such as cytokine release syndrome and neurotoxicity, which pose challenges for safe administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma. Jain, MD., Bachmeier, CA., Phuoc, VH., et al.[2020]

Yescarta (axicabtagene ciloleucel) is an engineered T-cell therapy that showed a 66% overall response rate and a 47% complete response rate in treating relapsed or refractory diffuse large B-cell lymphoma, based on a phase II study with a median follow-up of 15.1 months.

The therapy was associated with manageable adverse events, including cytokine release syndrome and neurological issues, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma. Papadouli, I., Mueller-Berghaus, J., Beuneu, C., et al.[2022]

In the ZUMA-12 study involving 40 patients with high-risk large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated a high complete response rate of 78% and an overall response rate of 89%, indicating its effectiveness as a first-line treatment.

The safety profile of axi-cel was manageable, with only 8% of patients experiencing severe cytokine release syndrome and 23% experiencing neurological events, and no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Neelapu, SS., Dickinson, M., Munoz, J., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7024

Real-world outcomes of axicabtagene ciloleucel (axi-cel) ... Double-/triple-hit lymphoma was seen in 12/50 pts (24%), and 51/58 (88%) had Stage III/IV disease. CNS sites involved preinfusion were brain (51 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04608487

Study Details | NCT04608487 | Axi-cel in CNS Lymphoma This study will examine the safety and efficacy of axi-cel in participants who either currently or previously had had central nervous system involvement of ...

3. yescartahcp.com yescartahcp.com/large-b-cell-lymphoma/real-world-evidence

Real World Evidence | YESCARTA® (axicabtagene ciloleucel) Real world data showing the benefits of YESCARTA® and how patients received the therapy. See Prescribing Information, BOXED WARNING, and Medication Guide.

4. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/1060/491025/A-Pilot-Study-of-Axicabtagene-Ciloleucel-axi-cel

A Pilot Study of Axicabtagene Ciloleucel (axi-cel) for the ... Conclusion: Based on these results, axi-cel has an acceptable safety profile for the treatment of both primary and secondary CNSL with no ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12577247/

Effectiveness of axicabtagene ciloleucel versus conventional ... We conducted an external comparator arm study to compare overall survival (OS) and progression-free survival (PFS) in patients treated with axi-cel from ZUMA-12 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02348216

NCT02348216 | Study Evaluating the Safety and Efficacy of ... Axicabtagene Ciloleucel (Axi-Cel) In Refractory Large B Cell Lymphoma: Outcomes in Patients ≥ or < 65 Years of Age in the Pivotal Phase 1/2 ZUMA-1 Study.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6990602/

Safety and efficacy of axicabtagene ciloleucel in refractory ... We provide an overview of axi-cel therapy, including efficacy and safety data, along with a practical discussion of current treatment considerations.