Tisagenlecleucel Safety for Cancer

Recruiting at 54 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

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety of tisagenlecleucel that is out of specification( OOS) for release as commercial product. Specifically, this study will evaluate the safety of CTL019 in the patients treated within the approved label by Japan Health Authority in Part 2. Only for Part 1, in addition to safety, key efficacy of CTL019 will also be evaluated.

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.

What data supports the effectiveness of the treatment Tisagenlecleucel (Kymriah) for cancer?

Tisagenlecleucel has shown an 81% response rate in children with relapsed or chemotherapy-resistant B-cell acute lymphoblastic leukemia and a 60% overall response rate in adults with relapsed or refractory large B-cell lymphoma, indicating its effectiveness in treating these types of cancer. ^{1 2 3 4 5}

Is tisagenlecleucel generally safe for humans?

Tisagenlecleucel, a CAR T-cell therapy, has been associated with serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Additionally, there are cardiac risks, including life-threatening events, that should be considered when using this treatment. ^{1 3 6 7 8}

How is the treatment Tisagenlecleucel unique for cancer?

Tisagenlecleucel is a unique treatment because it is a type of CAR T-cell therapy that uses genetically modified T-cells to target and destroy cancer cells, specifically those expressing the CD19 protein. This approach is different from traditional chemotherapy as it involves reprogramming the patient's own immune cells to fight cancer, offering hope for patients with relapsed or refractory B-cell malignancies. ^{1 3 6 7 9}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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]

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]

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]

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]

References

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

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia. [2021]

2. United States 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. [2023]

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

Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel. [2023]

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

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

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

Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study. [2023]

9. 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]