CART19 for Acute Lymphoblastic Leukemia

Overseen By Melissa S Varghese, B.A.

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Stephan Grupp MD PhD

Must not be taking: Systemic steroids

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

133 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, four-cohort, phase 2 study to determine the efficacy of CART19 in pediatric and young adult patientswith hypodiploid (Cohort A) or t(17;19) B-ALL (Cohort B), infants with very high risk KMT2A B-ALL (Cohort C), and in patients with central nervous system (CNS) relapse who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) (Cohort D).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use systemic steroids at the time of cell infusion or collection. Other medications might be allowed, so it's best to discuss your specific situation with the trial team.

What data supports the effectiveness of the treatment Murine CART19, tisagenlecleucel, Kymriah for Acute Lymphoblastic Leukemia?

Tisagenlecleucel, a part of the treatment, has shown high rates of complete remission in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in several studies, leading to its approval for use in these patients. ^{1 2 3 4 5}

Is tisagenlecleucel (CART19) safe for humans?

Tisagenlecleucel (also known as CART19 or Kymriah) has been used in children and young adults with a type of leukemia, showing serious but mostly reversible side effects. It has been approved by the FDA, indicating it has been evaluated for safety in humans. ^{1 2 3 4 6}

What makes the treatment tisagenlecleucel unique for acute lymphoblastic leukemia?

Tisagenlecleucel is a unique treatment for acute lymphoblastic leukemia because it is a CAR T-cell therapy that specifically targets CD19, a protein on the surface of cancer cells, and is approved for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia. This therapy can lead to durable remission in patients who have not responded to standard treatments. ^{1 2 4 5 7}

Research Team

Stephan Grupp, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Amanda DiNofia, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for pediatric and young adult patients (0-29 years) with specific types of B-cell Acute Lymphoblastic Leukemia (B-ALL), including those with hypodiploid karyotype, t(17;19) translocation, high-risk KMT2A rearrangement, or CNS relapse without prior cranial radiation or bone marrow transplant. Participants must have CD19+ expression on leukemia cells and meet organ function criteria.

Inclusion Criteria

My leukemia cells test positive for CD19.

I have B-cell Acute Lymphoblastic Leukemia that is CD19 positive.

I am between 0 and 29 years old.

Exclusion Criteria

I have not had brain radiation or bone marrow transplant for my current CNS relapse.

I am HIV positive.

I do not have any ongoing infections that aren’t responding to treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CART19 therapy targeting CD19 in pediatric and young adult patients with specific B-ALL subtypes

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including relapse-free survival and event-free survival assessments

1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Murine CART19

Trial Overview The study tests the effectiveness of Murine CART19 therapy in four different patient cohorts with various high-risk conditions of B-ALL. It's an open-label phase 2 trial where all participants receive the experimental treatment to see how well it works against their leukemia.

Participant Groups

Group I: Subjects with t(17;19) B-ALL Experimental Treatment 1 Intervention

Group II: Subjects with hypodiploid B-ALL Experimental Treatment 1 Intervention

Group III: Subjects with central nervous system (CNS) relapse Experimental Treatment 1 Intervention

who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT)

Group IV: Infant subjects with very high risk KMT2A B-ALL Experimental Treatment 1 Intervention

Murine CART19 is already approved in European Union, United States for the following indications:

Approved in European Union as tisagenlecleucel for:

• B-cell acute lymphoblastic leukemia (ALL)
• Diffuse large B-cell lymphoma (DLBCL)

Approved in United States as tisagenlecleucel for:

• B-cell precursor acute lymphoblastic leukemia (ALL)
• Diffuse large B-cell lymphoma (DLBCL)

Who Is Running the Clinical Trial?

Stephan Grupp MD PhD

Lead Sponsor

Trials

5

Recruited

370+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

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 CAR T cell therapy for relapsed/refractory B cell acute lymphoblastic leukemia, showed a high incidence of grade 3/4 adverse events (77% of patients), including cytokine-release syndrome (79%) and prolonged cytopenias (40%).

Despite the significant adverse events, the therapy led to complete remission in patients, with effective management of complications such as CRS using tocilizumab and corticosteroids, and a low incidence of severe infections after one year due to immunoglobulin replacement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. Levine, JE., Grupp, SA., Pulsipher, MA., et al.[2022]

Tisagenlecleucel, a CAR-T cell therapy, shows high overall remission rates of 69% to 93% in patients with relapsed/refractory B-cell acute lymphoblastic leukemia, with durable 12-month relapse-free survival rates of 55% to 59%.

However, the treatment is associated with significant risks, including potentially life-threatening cytokine release syndrome in 77% to 100% of patients and neurotoxicity in 31% to 45%, highlighting the need for careful patient selection and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Acute Lymphoblastic Leukemia: A Review of the Literature and Practical Considerations. Halford, Z., Anderson, MK., Bennett, LL., et al.[2021]

In a global study involving 75 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), the CAR T-cell therapy tisagenlecleucel achieved an impressive overall remission rate of 81% within 3 months, with all responders showing no minimal residual disease.

While 73% of patients experienced serious adverse events, including cytokine release syndrome in 77% and neurologic events in 40%, these effects were mostly manageable and reversible, indicating that tisagenlecleucel can provide durable remission despite the risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. Maude, SL., Laetsch, TW., Buechner, J., 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]

Tisagenlecleucel (Kymriah) is an effective treatment for B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old, achieving a complete remission rate of 63% in a study of 63 participants, with all remissions showing minimal residual disease (MRD) below 0.01%.

While the treatment shows promise, it is associated with serious side effects, including cytokine release syndrome (79%) and neurologic events (65%), but the overall benefit-risk profile is considered acceptable for patients with resistant forms of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. O'Leary, MC., Lu, X., Huang, Y., et al.[2020]

In a study of 14 infants with B-cell acute lymphoblastic leukemia (B-ALL) treated with tisagenlecleucel, 64% achieved minimal residual disease-negative remission, indicating significant efficacy of this CAR T-cell therapy in a population previously excluded from clinical trials.

The therapy was generally well-tolerated, with only 3 patients experiencing severe cytokine release syndrome and no reports of neurotoxicity, suggesting that tisagenlecleucel is a safe treatment option for infants with this aggressive form of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world use of tisagenlecleucel in infant acute lymphoblastic leukemia. Moskop, A., Pommert, L., Baggott, C., et al.[2022]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. [2022]

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

Tisagenlecleucel in Acute Lymphoblastic Leukemia: A Review of the Literature and Practical Considerations. [2021]

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

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. [2020]

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

Real-world use of tisagenlecleucel in infant acute lymphoblastic leukemia. [2022]