CAR T-Cell Therapy for Central Nervous System Lymphoma

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

18 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment Axicabtagene Ciloleucel (Yescarta, KTE-C19, Axi-cel) for Central Nervous System Lymphoma?

Axicabtagene ciloleucel (axi-cel) has shown effectiveness in treating relapsed or refractory large B-cell lymphoma, a type of aggressive non-Hodgkin's lymphoma, as demonstrated in clinical trials. Additionally, similar CAR T-cell therapies have shown potential in treating lymphomas with central nervous system involvement, suggesting that axi-cel might also be effective in this context. ^{1 2 3 4 5}

Is CAR T-Cell Therapy (Axicabtagene Ciloleucel) safe for humans?

Axicabtagene ciloleucel, a CAR T-cell therapy, has been studied for safety in treating certain types of lymphoma. Common side effects include cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), but these are generally manageable. No treatment-related deaths were reported in the studies, indicating a manageable safety profile. ^{2 4 6 7 8}

How is the treatment Axicabtagene Ciloleucel unique for central nervous system lymphoma?

Axicabtagene Ciloleucel is a unique treatment because it uses the patient's own T-cells, which are modified to target and destroy cancer cells expressing the CD19 protein, a feature not present in traditional chemotherapy. This approach, known as CAR T-cell therapy, represents a novel way to treat cancers that have not responded to other treatments. ^{1 2 4 9 10}

What is the purpose of this trial?

This research is being done to test the safety and effectiveness of axicabtagene ciloleucel (axi-cel), an anti-CD19 directed chimeric antigen receptor (CAR) T-cell therapy in treating relapsed/refractory central nervous system (CNS) lymphoma, systemic lymphoma with concurrent CNS lymphoma, or systemic lymphoma with a history of treated CNS lymphoma, and to better understand what causes neurological toxicity following treatment with axi-cel. The names of the study drug(s) involved in this study are: * axicabtagene ciloleucel (axi-cel) * ludarabine will be given with axicel to help axicel work more effectively * cyclophosphamide will be given with axicel to help axicel work more effectively

Research Team

Caron Jacobson

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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 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]

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]

References

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

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. [2023]

2. United States 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. [2021]

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

The Cerebroventricular Environment Modifies CAR T Cells for Potent Activity against Both Central Nervous System and Systemic Lymphoma. [2022]

4. New Zealand 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. [2020]

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

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. [2022]

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

Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. [2023]

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

EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma. [2022]

8. United States 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. [2021]

9. United States 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. [2020]

10. Spain pubmed.ncbi.nlm.nih.gov

Axicabtagene ciloleucel for the treatment of relapsed/refractory B-cell non-Hodgkin's lymphomas. [2018]