Tisagenlecleucel for Acute Lymphoblastic Leukemia

(CASSIOPEIA Trial)

Recruiting at 76 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must not be taking: Tyrosine kinase inhibitors, Anti-CD19 therapy

Disqualifiers: Philadelphia chromosome, Hypodiploid, Burkitt's, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 29

121 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who received first-line treatment and are EOC MRD positive. The study will have the following sequential phases: screening, pre-treatment, treatment \& follow-up, and survival. After tisagenlecleucel infusion, patient will have assessments performed more frequently in the first month and then at Day 29, then every 3 months for the first year, every 6 months for the second year, then yearly until the end of the study. Efficacy and safety will be assessed at study visits and as clinically indicated throughout the study. The study is expected to end in approximately 8 years after first patient first treatment (FPFT). A post-study long term follow-up safety will continue under a separate protocol per health authority guidelines.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that prior induction and consolidation chemotherapy is allowed, which suggests some treatments may be continued. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Tisagenlecleucel for Acute Lymphoblastic Leukemia?

Tisagenlecleucel has shown effectiveness in treating children and young adults with relapsed or hard-to-treat B-cell acute lymphoblastic leukemia, with a complete response rate of 81% and a 12-month overall survival rate of 76%. ^{1 2 3 4 5}

Is Tisagenlecleucel safe for treating acute lymphoblastic leukemia?

Tisagenlecleucel has been found to be generally safe in treating acute lymphoblastic leukemia, with some patients experiencing serious side effects like cytokine release syndrome (a severe immune reaction) but no reported neurotoxicity (nerve damage). ^{2 4 6 7 8}

How is 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, which means it uses genetically modified T-cells (a type of immune cell) to specifically target and kill cancer cells. This approach is different from traditional chemotherapy or radiation, as it harnesses the body's own immune system to fight the cancer. ^{2 3 4 6 8}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for young people (1-25 years old) with high-risk B-cell Acute Lymphoblastic Leukemia who've had first-line treatment but still have detectable cancer cells. They need to be generally healthy, with good heart, kidney, liver function and no severe breathing problems.

Inclusion Criteria

My leukemia is CD19 positive.

oxygen saturation of > 90% on room air

My ALT levels are within 5 times the normal limit for my age.

Exclusion Criteria

My cancer cells have fewer than 44 chromosomes or a low DNA index.

My bone marrow is still highly affected by cancer after initial treatment.

I have been diagnosed with Burkitt's lymphoma/leukemia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Preparation phase before receiving tisagenlecleucel infusion

2-4 weeks

Treatment & Follow-up

Participants receive tisagenlecleucel infusion and are monitored frequently in the first month, then at Day 29, every 3 months for the first year, every 6 months for the second year, and yearly thereafter

8 years

Frequent visits in the first month, then at Day 29, every 3 months for the first year, every 6 months for the second year, then yearly

Survival

Monitoring of overall survival and disease-free survival

4-5 years

Post-study Long-term Follow-up

Long-term safety follow-up under a separate protocol per health authority guidelines

8 years

Treatment Details

Interventions

• Tisagenlecleucel

Trial Overview The study tests the safety and effectiveness of a therapy called tisagenlecleucel (CTL019) in patients after initial leukemia treatments. It's an open-label phase II trial where participants are closely monitored over several phases including screening, pre-treatment, treatment & follow-up.

Participant Groups

Group I: Single dose of CTL019 Experimental Treatment 1 Intervention

Based on the subject's weight one of two possible dose ranges will be prepared for the subject: Subjects ≤ 50 kg: 0.2 to 5.0 x 10(6) CAR-positive viable T cells per kg body weight OR Subjects \> 50 kg: 0.1 to 2.5 x 10(8) CAR-positive viable T cells

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

Approved in United States as Kymriah for:

• B-cell acute lymphoblastic leukemia (ALL) in patients up to 25 years old
• 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 Kymriah for:

• B-cell acute lymphoblastic leukemia (ALL) in patients up to 25 years old
• Relapsed or refractory diffuse 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

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Children's Oncology Group

Collaborator

Trials

467

Recruited

241,000+

Findings from Research

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 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-ALL, showed an 85% complete response rate in infused patients and a 12-month overall survival rate of 72%, indicating its efficacy in treating this condition.

Patients with a high disease burden before treatment had significantly worse outcomes and higher rates of severe side effects, highlighting the importance of disease status in predicting treatment success and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report. Schultz, LM., Baggott, C., Prabhu, S., et al.[2023]

Tisagenlecleucel (tisa-cel) is an effective CAR-T therapy for patients with relapsed/refractory follicular lymphoma (R/R FL), showing durable remissions even in high-risk patients, as confirmed by the pivotal ELARA study.

The therapy has a manageable toxicity profile, making it a viable option for patients who have undergone two lines of systemic therapies, leading to its FDA approval for this indication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel: CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma. Saha, A., Jhaveri, K., Sarfraz, H., et al.[2023]

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]

The total estimated cost for treating pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia using tisagenlecleucel is $612,779, which includes significant additional costs beyond the drug's list price of $475,000.

Adverse event management and inpatient admissions were the main contributors to the additional costs, highlighting the importance of considering these factors in the overall economic evaluation of tisagenlecleucel treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimation of Total Costs in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Receiving Tisagenlecleucel from a U.S. Hospital's Perspective. Yang, H., Hao, Y., Qi, CZ., et al.[2023]

References

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

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

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

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

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

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

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

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel: CAR-T cell therapy for adult patients with relapsed or refractory follicular lymphoma. [2023]

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]

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

Estimation of Total Costs in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Receiving Tisagenlecleucel from a U.S. Hospital's Perspective. [2023]