Tisagenlecleucel Safety for Cancer

Recruiting at 69 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of tisagenlecleucel, a type of CAR T-cell therapy, for certain blood cancers. It targets individuals whose cancer treatment product did not meet usual standards but might still offer more benefits than risks. The trial includes adults with types of non-Hodgkin lymphoma (NHL) and large B-cell lymphoma (LBCL), as well as young people with a certain type of acute lymphoblastic leukemia (pALL). It suits those facing serious or life-threatening cancers who cannot undergo another round of cell collection for treatment. As a Phase 3 trial, this study represents the final step before FDA approval, providing patients access to potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Research has shown that tisagenlecleucel, a type of CAR-T cell therapy, is generally well-tolerated by patients. In studies for relapsed or refractory large B-cell lymphoma (r/r LBCL), some side effects have been noted, but overall, it maintains a good safety record. Serious side effects can include cytokine release syndrome (where the immune system becomes too active) and neurotoxicity (which affects the brain and nerves), but these are carefully monitored and managed during treatment.

For relapsed or refractory non-Hodgkin lymphoma (r/r NHL), similar safety results have been observed. The benefits of the treatment often outweigh these potential risks, as it specifically targets and destroys cancer cells.

In children with relapsed or refractory acute lymphoblastic leukemia (r/r pALL), tisagenlecleucel has also demonstrated a manageable safety profile. The side effects are similar to those in adults and receive special care.

Overall, thorough studies support the safety of this treatment in these conditions, and it remains a promising option for patients with these challenging cancers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Tisagenlecleucel is unique because it's a type of CAR-T cell therapy, which stands apart from traditional chemotherapy or radiation treatments for certain cancers. This therapy uses a patient's own T cells, genetically modifying them to better recognize and attack cancer cells. Researchers are excited because it offers a targeted approach, potentially leading to fewer side effects and improved outcomes for patients with difficult-to-treat lymphomas and leukemias. Unlike standard treatments that affect both healthy and cancerous cells, tisagenlecleucel is designed to specifically target cancer cells, providing a more precise and personalized treatment option.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that tisagenlecleucel, a type of CAR T-cell therapy, effectively treats certain relapsed or hard-to-treat cancers. In this trial, participants will be divided into groups based on their specific cancer type. For those with relapsed or refractory large B-cell lymphoma (LBCL), studies indicate consistent response rates, with patients living a median of 14 months after trying at least two other treatments. Participants with relapsed or refractory non-Hodgkin lymphoma (NHL) may also benefit, as this treatment has proven effective with better safety outcomes than traditional therapies. For children and young adults with relapsed or refractory acute lymphoblastic leukemia (pALL), tisagenlecleucel has led to long-lasting remission and long-term benefits. Overall, tisagenlecleucel targets and destroys cancerous B cells, offering hope when other treatments have not worked. ^{1 2 3 4 6}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for patients with certain types of B-cell lymphoma or acute lymphoblastic leukemia whose tisagenlecleucel treatment doesn't meet commercial standards but isn't unsafe. They must understand the study, not have hepatitis B/C, CNS lymphoma, HIV, uncontrolled infections, be pregnant/nursing, or have conditions affecting safety assessment.

Inclusion Criteria

My doctor thinks a second leukapheresis is not right for me.

The materials used in my treatment are considered safe.

My tisagenlecleucel treatment was not made to commercial standards.

Exclusion Criteria

I understand that there are no specific exclusions for part 2, but treatment must follow the latest CTL019 guidelines.

I have active Hepatitis B or C.

I have been diagnosed with lymphoma in my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of CTL019

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months for Part 1, 1 day for Part 2

What Are the Treatments Tested in This Trial?

Interventions

• CTL019
• Tisagenlecleucel

Trial Overview The trial tests the safety and some efficacy of CTL019 (tisagenlecleucel) that's out of specification for commercial release in Japan. Part 1 looks at both safety and key effects; Part 2 focuses on safety within approved use.

How Is the Trial Designed?

Group I: Group C: r/r NHL Experimental Treatment 1 Intervention

Adult patients with r/r NHL in consistent with the Health Authority approved indication in the package insert for CTL019 in Japan whose final manufactured product is OOS for commercial release, but it is considered that the benefit-risk profile may remain favorable and the usual expected benefits of infusing such a product outweigh the potential risks for the patient.

Group II: Group B: r/r LBCL Experimental Treatment 1 Intervention

Adult patients with r/r LBCL including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma, that is consistent with the Health Authority-approved indication in the package insert for CTL019 in the respective country/region whose final manufactured product is OOS for commercial release, but it is considered that the benefit-risk profile may remain favorable and the usual expected benefits of infusing such a product outweigh the potential risks for the patient.

Group III: Group A: pALL Experimental Treatment 1 Intervention

Pediatric/young adult patients with r/r pALL who meet the indication in the Health Authority-approved CTL019 package insert in the respective country/region whose final manufactured product is OOS for commercial release, but it is considered that the benefit-risk profile may remain favorable and the usual expected benefits of infusing such a product outweigh the potential risks for the patient.

CTL019 is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Kymriah for:

• B-cell acute lymphoblastic leukemia (ALL)
• Large B-cell lymphoma
• Follicular lymphoma

Approved in European Union as Kymriah for:

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

Approved in Japan as Kymriah for:

• B-cell acute lymphoblastic leukemia (ALL)
• Large B-cell lymphoma
• Follicular lymphoma

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

Published Research Related to This Trial

YTB323, a new CAR T-cell therapy targeting CD19, demonstrated high overall response rates and durable complete remissions in a first-in-human study, indicating its potential effectiveness in treating certain cancers.

The therapy was shown to have a good safety profile and required cell doses that were up to 25-fold lower than those used in the previously established treatment, tisagenlecleucel, suggesting a more efficient approach to CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Express Delivery of Next-Generation CAR T Cells with Preserved Naive and Stemness Phenotypes for the Treatment of Aggressive Lymphomas. Wang, M.[2023]

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]

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]

In a study of 91 patients with relapsed/refractory large B-cell lymphoma (LBCL), treatment with the CAR T-cell therapy tisagenlecleucel (tisa-cel) resulted in a best overall response rate of 60% and a complete response rate of 32%, indicating its efficacy in a real-world setting.

The safety profile of tisa-cel was manageable, with only 5% of patients experiencing severe cytokine release syndrome and 1% experiencing neurotoxicity, suggesting that it can be safely administered in standard-of-care settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Iacoboni, G., Villacampa, G., Martinez-Cibrian, N., et al.[2021]

The analysis of data from the FDA's Adverse Event Reporting System revealed that the CAR-T product Tisagenlecleucel had a notably high rate of severe outcomes, with 53.24% of cases resulting in death and 13.39% being life-threatening.

Different CAR-T therapies, particularly Axicabtagene ciloleucel and Tisagenlecleucel, showed varying frequencies and types of cardiac events, highlighting the need for careful monitoring of cardiac risks associated with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study. Zhai, Y., Hu, F., Zhu, B., et al.[2023]

In a study of 37 adult patients undergoing CAR T-cell therapy for relapsed/refractory large B-cell lymphoma, 24% had their manufactured tisagenlecleucel (tisa-cel) classified as out-of-commercial specification (OOS).

Among the patients with OOS tisa-cel, 44% received academic point-of-care CAR T-cell therapy as a salvage option, with 75% of those achieving a complete response, highlighting the potential effectiveness of alternative therapies in this scenario.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel. Fried, S., Shouval, R., Varda-Bloom, N., et al.[2023]

In adults with relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (ALL), the fractionated dosing strategy of the anti-CD19 CAR T-cell therapy, tisagenlecleucel (CTL019), resulted in a remarkable 90% complete remission rate and a 73% overall survival rate at 2 years.

The optimized dosing approach, which included managing cytokine release syndrome (CRS) effectively, demonstrated that safety can be improved without sacrificing the treatment's efficacy, making it a promising option for adult patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia. Frey, NV., Shaw, PA., Hexner, EO., et al.[2021]

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]

Chimeric antigen receptor-modified T-cells (CAR-T), specifically tisagenlecleucel, have shown significant efficacy in treating relapsed/refractory acute lymphoblastic leukemia (ALL), representing a major advancement in therapy for this challenging patient group.

Management of toxicities, particularly cytokine release syndrome and neurotoxicity, is crucial for patient safety during CAR-T treatment, with the use of IL-6 receptor inhibitors being an important part of this management strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Vairy, S., Garcia, JL., Teira, P., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10294746/

Kymriah® (tisagenlecleucel) – An overview of the clinical ... Kymriah® (tisagenlecleucel), a CD19-directed CAR-T, was the first cell-based gene therapy approved by the US Food and Drug Administration (FDA) in 2017 for the ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1804980

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse ... The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02445248

NCT02445248 | Study of Efficacy and Safety of CTL019 in ... This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

4. kymriah-hcp.com kymriah-hcp.com/diffuse-large-b-cell-lymphoma-adults/efficacy

Efficacy Data | KYMRIAH® (tisagenlecleucel) for DLBCL | HCP KYMRIAH demonstrated consistent response rates across high-risk patient subgroups with non-Hodgkin lymphoma that have relapsed or are refractory after ≥2 lines ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12476396/

Clinical outcomes of tisagenlecleucel in relapsed/refractory ... Consequently, Tisa-cel could recommended as a third-line treatment option, as it offers a median overall survival (OS) of 14 months in patients with relapsed or ...

6. fda.gov fda.gov/media/107296/download

KYMRIAH - Package Insert and Medication Guide The safety data described in the WARNINGS AND PRECAUTIONS and in this section reflect exposure to KYMRIAH in three non-randomized, single-arm studies in which ...