CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

Overseen By DL-CCT-Coordinators

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Must not be taking: Anticoagulants

Disqualifiers: CNS disorders, Cardiac disease, Infections, others

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

Compensation: Varies

Number of Visits: 18

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treat acute lymphoblastic leukemia (ALL) that hasn't responded to standard treatments or has returned. It combines CAR T-cell therapy (Chimeric Antigen Receptor T-Cell Therapy), where immune cells are engineered to target cancer cells, with chemotherapy. The goal is to determine the most effective dose and understand potential side effects. Suitable candidates include children or young adults with ALL whose disease has returned or not responded to other treatments and who have CD19 proteins on their cancer cells. 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 need to stop my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but it does mention that certain chemotherapy drugs should be stopped at least one week before apheresis (a procedure to collect blood cells). It's best to discuss your specific medications with the trial team to get a clear answer.

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

Research has shown that CAR T-cell therapy is a strong option for treating certain cancers, such as B-cell and plasma cell cancers. Many patients have benefited from this treatment, which uses specially modified T cells to target cancer cells. However, like any treatment, some patients may experience side effects.

Chemotherapy drugs like fludarabine phosphate and cyclophosphamide have been used for a long time and are well-understood. They stop cancer cells from growing or spreading. While these drugs can be effective, they can also cause side effects.

Since this trial is in its early stages, the main goal is to find the best dose and assess how well people handle the treatment. Safety and side effects are being closely monitored. Prospective participants should discuss with their doctor to understand what this might mean for them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CAR T-Cell Therapy for Acute Lymphoblastic Leukemia (ALL) because it offers a unique approach by harnessing the patient's own immune system to fight cancer. Unlike traditional chemotherapy, which attacks cancer cells—and healthy cells—indiscriminately, CAR T-Cell Therapy specifically targets and destroys leukemia cells using engineered T-cells designed to recognize proteins like CD19 and CD22 on the surface of these cancer cells. This therapy is particularly promising because it has the potential to provide long-lasting remission, even for patients who have not responded to other treatments. Additionally, this personalized treatment can be administered in a matter of minutes, significantly reducing the treatment burden compared to prolonged chemotherapy sessions.

What evidence suggests that CAR T-cell therapy might be an effective treatment for acute lymphoblastic leukemia?

Research has shown that CAR T-cell therapy, which participants in this trial will receive, is a promising treatment for certain blood cancers, such as B-cell acute lymphoblastic leukemia. This therapy helps the immune system find and attack cancer cells by targeting specific proteins, like CD19 and CD22, on these cells. Many patients have benefited from CAR T-cell therapy, with some experiencing long-term remission. The therapy can destroy cancer cells and may remain active in the body for months, possibly preventing the cancer from returning. While this approach is promising, its effectiveness can vary, and the treatment may have side effects. ^{1 2 6 7 8}

Who Is on the Research Team?

Crystal Mackall, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 30 with B-cell acute lymphoblastic leukemia that's resistant or has returned after treatment. They should have tried at least two therapies, be free of uncontrolled infections, not pregnant or breastfeeding, and without severe heart conditions. Participants must also have no history of certain other diseases within the last three years.

Inclusion Criteria

Must have evaluable or measurable disease according to the revised IWG Response Criteria for Malignant Lymphoma

My condition worsened after a stem cell transplant.

My minimal residual disease has been confirmed positive twice, at least 4 weeks apart.

Exclusion Criteria

I do not have brain disorders that could affect nerve damage assessment.

Unlikely to complete all protocol-required study visits or procedures

My ALL has come back or didn't respond to treatment, and is only in my testicles.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2

1 week

3 visits (in-person)

CAR T Cell Treatment

Participants receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Additional doses may be given if beneficial and no unacceptable side effects occur

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Daily until day 14, twice weekly until day 28, at 2 and 3 months, every 3 months until month 12, every 6-12 months up to year 5, then annually for years 6-15

What Are the Treatments Tested in This Trial?

Interventions

• Chimeric Antigen Receptor T-Cell Therapy
• Cyclophosphamide
• Fludarabine Phosphate

Trial Overview The study tests different doses of CD19/CD22 CAR T cells combined with chemotherapy (fludarabine phosphate and cyclophosphamide) in patients whose leukemia expresses CD19 proteins. It aims to find the best dose that is effective while monitoring side effects.

How Is the Trial Designed?

Group I: Treatment (CD19/CD22-CAR T cells, chemotherapy) Experimental Treatment 5 Interventions

Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and cyclophosphamide IV over 60 minutes on day -2. Patients then receive CD19/CD22-CAR T cells IV over 10-20 minutes on day 0. Patients that benefited from the first dose of CD19/CD22-CAR T cells, had no unacceptable side effects, and have enough cells left over may receive 2 or 3 additional doses of CD19/CD22-CAR T cells.

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?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

Published Research Related to This Trial

Tisagenlecleucel, a type of chimeric antigen receptor T-cell therapy, has shown significant improvements in survival rates for pediatric and young adult patients with refractory or relapsed acute lymphoblastic leukemia (ALL), with some patients achieving remissions lasting years.

This therapy represents a major advancement in treatment options, as traditional chemotherapy and targeted therapies have low remission rates, making tisagenlecleucel a potential game-changer in managing this previously fatal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel for the treatment of B-cell acute lymphoblastic leukemia. Leahy, AB., Elgarten, CW., Grupp, SA., et al.[2022]

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]

CAR T cell therapy, particularly with the FDA-approved product tisagenlecleucel, has shown significant response rates in treating relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) in patients under 26 years old.

Despite its effectiveness, challenges such as high relapse rates, potential toxicities, and logistical issues in the therapy's production and administration remain significant barriers to its widespread application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience of CAR T cells for B cell acute lymphoblastic leukemia. Fabrizio, VA., Curran, KJ.[2022]

In a study of 79 pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia, those who responded to the CAR T-cell therapy tisagenlecleucel showed approximately double the expansion of the therapy in their blood compared to nonresponders, indicating a strong correlation between cellular expansion and treatment efficacy.

The therapy demonstrated persistence in responders for over two years, and its expansion continued even after treatment with tocilizumab, which is used to manage cytokine release syndrome, suggesting that tisagenlecleucel can remain effective despite potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Mueller, KT., Waldron, E., Grupp, SA., et al.[2020]

Tisagenlecleucel is the first chimeric antigen receptor T-cell therapy approved by the FDA for treating B-cell precursor acute lymphoblastic leukemia in patients up to 25 years old.

This therapy is specifically designed for patients who have not responded to standard treatments or have relapsed at least twice, highlighting its role as a critical option for difficult-to-treat cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Ever CAR T-cell Therapy Approved in U.S. [2021]

Tisagenlecleucel and axicabtagene ciloleucel are groundbreaking CAR-T cell therapies that have shown high effectiveness in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) and certain types of B-cell non-Hodgkin lymphomas.

This review highlights the challenges faced by physicians in administering these therapies and discusses future directions for research and treatment in the field of immune and cellular therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. Mohty, M., Gautier, J., Malard, F., et al.[2022]

Tisagenlecleucel is the first FDA-approved CD19-targeted CAR T cell therapy specifically for pediatric patients with pre-B-cell acute lymphoblastic leukemia (B-ALL), showing excellent responses in a multicenter phase II trial for those with highly refractory disease.

While CAR T cell therapy can lead to durable remissions in many patients, close monitoring for unique toxicities such as cytokine release syndrome and neurotoxicity is essential after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 CAR T Cells for the Treatment of Pediatric Pre-B Cell Acute Lymphoblastic Leukemia. Pacenta, HL., Laetsch, TW., John, S.[2020]

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, a CAR T-cell therapy approved for relapsed/refractory acute lymphoblastic leukemia in patients up to 25 years old, shows remarkable efficacy with over 80% complete response rates and more than 60% six-month relapse-free survival in a challenging patient population.

While tisagenlecleucel offers significant therapeutic benefits, it carries risks of severe side effects like cytokine release syndrome and neurotoxicity, necessitating careful monitoring and management strategies, including the use of tocilizumab for CRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel: The First CAR on the Highway to Remission for Acute Lymphoblastic Leukemia. Freyer, CW.[2020]

In a case study of a patient with relapsed/refractory B-cell acute lymphoblastic leukemia, lymphodepletion using clofarabine and cyclophosphamide before CAR-T-cell therapy led to successful remission, demonstrating clofarabine's potential as an alternative to fludarabine.

Clofarabine did not impair the effectiveness of the CAR-T cells, as evidenced by the patient's cytokine release syndrome and the absence of minimal residual disease, indicating a successful treatment outcome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. Foti, A., Stein, D., Seidel, D., et al.[2023]

CAR T-cell therapies, particularly axicabtagene ciloleucel (axi), show a greater survival advantage in adult patients with acute lymphoblastic leukemia (ALL) compared to those with relapsed/refractory large B-cell lymphoma (LBCL).

In patients with LBCL, axicabtagene ciloleucel (axi) provides a more substantial survival benefit compared to tisagenlecleucel (tisa), indicating differences in efficacy between these CAR T-cell products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Large B-Cell Lymphoma: Analysis of Overall Survival Based on Reconstructed Patient-Level Data. Messori, A., Chiumente, M., Mengato, D.[2022]

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]

Citations

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Chimeric Antigen Receptor (CAR) T-Cell Therapy in ... CAR T-cell therapy has become a powerful treatment option in B-cell and plasma cell malignancies, and many patients have benefited from its use.

2. bloodcancerunited.org bloodcancerunited.org/blood-cancer-care/adults/types-blood-cancer-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy

Chimeric antigen receptor (CAR) T-cell therapy CAR T cells may help guard against recurrence. CAR T cells may not only eradicate all cancer cells in the body, but they may remain in the body months after the ...

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CAR-T cell therapy for cancer: current challenges and ... This review begins with a comprehensive overview of CAR-T cell therapy for cancer, covering the structure of CAR-T cells and the history of their clinical ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9354650/

Clinical Trials for Chimeric Antigen Receptor T-Cell Therapy Currently, four CAR-T-cell therapies are approved for B-cell NHL: lisocabtagene maraleucel (Breyanzi™), tisagenlecleucel (Kymriah™), brexucabtagene autoleucel ( ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1098301524023362

Economic Evaluations of Chimeric Antigen Receptor T-Cell ... This systematic review provides a comprehensive summary and critical evaluation of the available evidence on the economic value of CAR-T therapies.

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CAR-T cell therapy CAR-T cell therapy is a cancer treatment that takes cells from the body and genetically changes them so they can fight cancer.

7. cms.gov cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=291

Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers Use this page to view details for the Proposed Decision Memo for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N).

8. sciencedirect.com sciencedirect.com/science/article/pii/S2152265024001149

SOHO State of the Art Updates and Next Questions ... Chimeric antigen receptor T-cell (CAR-T) therapy has significantly impacted treatment algorithms and clinical outcomes for a variety of patients with ...