CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

Overseen by Crystal Mackall, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Crystal Mackall, MD

Must not be taking: Anticoagulants

Disqualifiers: CNS disorders, Cardiac disease, Infections, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial studies a new treatment combining modified immune cells and chemotherapy for children and young adults with difficult-to-treat leukemia. The immune cells are engineered to target and kill cancer cells, while chemotherapy helps them work more effectively.

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.

What data supports the effectiveness of the treatment Chimeric Antigen Receptor T-Cell Therapy for Acute Lymphoblastic Leukemia?

Research shows that CAR T-cell therapies like tisagenlecleucel and axicabtagene ciloleucel are highly effective for treating relapsed or refractory B-cell acute lymphoblastic leukemia, significantly improving survival rates and achieving long-term remissions in many patients. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for humans?

CAR T-cell therapy, including treatments like tisagenlecleucel and axicabtagene ciloleucel, has been approved for certain cancers and shows promising results, but it can cause serious side effects. Patients may experience cytokine release syndrome (a severe immune reaction), neurotoxicity (nerve damage), and infections, which require careful monitoring and management. ^{6 7 8 9 10}

How is CAR T-cell therapy different from other treatments for acute lymphoblastic leukemia?

CAR T-cell therapy is unique because it uses genetically modified T-cells (a type of immune cell) to specifically target and destroy cancer cells in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. This treatment is particularly effective for patients who have not responded to standard therapies, offering a new option for those with limited alternatives. ^{1 2 10 11 12}

Research Team

Crystal Mackall, MD

Principal Investigator

Stanford University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Chimeric Antigen Receptor T-Cell Therapy (CAR T-cell Therapy)
• Cyclophosphamide (Alkylating agents)
• Fludarabine Phosphate (Anti-metabolites)

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.

Participant Groups

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 Canada, Japan for the following indications:

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?

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

Findings from Research

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, 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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. [2022]

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

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel for the treatment of B-cell acute lymphoblastic leukemia. [2022]

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

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. [2023]

5. United States 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. [2022]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

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

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

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

9. 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]

10. Switzerland pubmed.ncbi.nlm.nih.gov

CD19 CAR T Cells for the Treatment of Pediatric Pre-B Cell Acute Lymphoblastic Leukemia. [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Clinical experience of CAR T cells for B cell acute lymphoblastic leukemia. [2022]

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

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