Tisagenlecleucel for B-Cell Lymphoma

(BELINDA Trial)

Recruiting at 90 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must not be taking: Anti-CD19, T cell therapy

Disqualifiers: CNS involvement, Cardiovascular conditions, 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: 6 weeks

331 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that only steroids and local irradiation are allowed for disease control before randomization, so you might need to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Tisagenlecleucel for B-Cell Lymphoma?

Tisagenlecleucel, a CAR T-cell therapy, has shown effectiveness in treating relapsed or refractory large B-cell lymphoma and follicular lymphoma, with studies reporting high response rates and manageable side effects. In particular, the ELARA study confirmed its efficacy in follicular lymphoma, leading to FDA approval for this condition. ^{1 2 3 4 5}

Is tisagenlecleucel (Kymriah) generally safe for humans?

Tisagenlecleucel (Kymriah) has been shown to have a manageable safety profile in treating relapsed or refractory large B-cell lymphoma, with serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity occurring in a small percentage of patients. It has been approved for use in certain types of lymphoma and leukemia, indicating that its safety has been evaluated and deemed acceptable for these conditions. ^{1 2 4 6 7}

How is the treatment Tisagenlecleucel unique for B-Cell Lymphoma?

Tisagenlecleucel is a unique treatment for B-Cell Lymphoma 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 attack cancer cells. This approach is different from traditional chemotherapy as it involves reprogramming the patient's own immune cells to fight the cancer, offering a personalized and potentially more effective treatment option for those with relapsed or refractory lymphoma. ^{1 2 3 7 8}

What is the purpose of this trial?

This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and tolerability of tisagenlecleucel to Standard Of Care in adult patients with aggressive B-cell Non-Hodgkin Lymphoma after failure of rituximab and anthracycline containing frontline immunochemotherapy.

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for adults with aggressive B-cell Non-Hodgkin Lymphoma who didn't respond well to initial treatments including rituximab and anthracycline. Participants need good organ function, no severe heart issues, and must not have had certain previous therapies like anti-CD19 therapy or allogeneic HSCT. They should be physically able to undergo the procedures involved.

Inclusion Criteria

Adequate organ function: Renal function defined as: Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 Hepatic function defined as: Alanine Transaminase (ALT) and Aspartate Transiminase (AST) ≤ 5 × ULN Total bilirubin ≤ 1.5 x ULN with the exception of patients with Gilbert syndrome who may be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin ≤1.5 × ULN Hematologic Function (regardless of transfusions) defined as: Absolute neutrophil count (ANC) >1000/mm3 Absolute lymphocyte count (ALC) >300/mm3 OR Absolute number of CD3+ T cells >150/mm3 (only for patients with non-historical apheresis) Platelets ≥50000/mm3 Hemoglobin >8.0 g/dl Adequate pulmonary function defined as: No or mild dyspnea (≤ Grade 1) Oxygen saturation measured by pulse oximetry > 90% on room air Forced expiratory volume in 1 s (FEV1) ≥ 50% and/or carbon monoxide diffusion test (DLCO) ≥50% of predicted level Must have a leukapheresis material of non-mobilized cells available for manufacturing.

My aggressive B-cell NHL has returned or worsened after initial treatment.

My disease shows active on PET and measurable on CT scans, and I'm mostly self-sufficient.

Exclusion Criteria

You have already received treatment with certain types of therapies or gene therapy products. You have received second-line anticancer therapy before being enrolled in this trial, except for steroids and local irradiation. You have active disease in your central nervous system, unless it has been effectively treated and local treatment was over 4 weeks ago. You have undergone allogeneic HSCT or have a significant active infection.

You have certain heart conditions such as recent heart attack, heart failure, or abnormal heart rhythms. Your heart's pumping ability is also below a certain level. You have a high risk for a dangerous heart rhythm disorder called Torsades de Pointes or have a history of long QT syndrome or sudden death in the family. You also have active neurological or cerebrovascular disorders.

There may be other requirements that you need to meet or avoid to be eligible for the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either tisagenlecleucel or standard of care treatment, including optional platinum-based immunochemotherapy and lymphodepleting chemotherapy

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Long-term follow-up

Participants are monitored for long-term outcomes such as event-free survival and overall survival

5 years

Treatment Details

Interventions

• Autologous Hematopoietic Stem Cell Transplant
• Immunochemotherapy
• Tisagenlecleucel

Trial Overview The study compares tisagenlecleucel (a type of immunotherapy) after optional chemotherapy to standard platinum-based immunochemotherapy followed by high dose chemo and stem cell transplant in patients responding to treatment. It's a phase III trial, meaning it's testing effectiveness on a larger scale.

Participant Groups

Group I: Tisagenlecleucel treatment strategy Experimental Treatment 1 Intervention

Patients received investigator's choice of optional platinum-based immunochemotherapy followed by lymphodepleting chemotherapy and a single dose of tisagenlecleucel

Group II: Standard of care treatment strategy Active Control 1 Intervention

Patients received investigator's choice of platinum-based immunochemotherapy followed in responding patients by high dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT)

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

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]

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]

CAR T cell therapy, specifically tisagenlecleucel, has significantly improved treatment outcomes for patients with relapsed or refractory diffuse large B cell lymphoma, showcasing its efficacy in this challenging condition.

The review also highlights the importance of understanding the biological mechanisms of tisagenlecleucel and its comparison to other CAR T therapies, as well as the financial considerations and ongoing clinical trials that may influence future treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating tisagenlecleucel and its potential in the treatment of relapsed or refractory diffuse large B cell lymphoma: evidence to date. Zavras, PD., Wang, Y., Gandhi, A., 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]

In a pivotal phase 2 study involving 93 adult patients with relapsed or refractory diffuse large B-cell lymphoma, CAR T-cell therapy with tisagenlecleucel achieved a best overall response rate of 52%, with 40% of patients experiencing complete responses.

The treatment demonstrated durable responses, with a 12-month relapse-free survival rate of 65%, and no deaths were attributed to the therapy itself, although some patients experienced significant adverse events like cytokine release syndrome and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Schuster, SJ., Bishop, MR., Tam, CS., et al.[2019]

Two CAR T cell therapies, Tisagenlecleucel and Axicabtagene ciloleucel, have been approved for treating specific types of blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma, in patients who have not responded to other treatments.

This review emphasizes the importance of recognizing and managing the toxicities associated with CAR T cell therapies, while also suggesting future strategies to reduce these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Toxicity: Current Management and Future Directions. Yáñez, L., Sánchez-Escamilla, M., Perales, MA.[2020]

In a study of 32 patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) treated with tisagenlecleucel (tisa-cel), the level of CAR-T cell expansion in the body after treatment was found to be a key predictor of therapy success, rather than the specific characteristics of the CAR-T cells themselves.

Patients who had a higher percentage of certain T cell types (CD8+CD45RA+CD27+) before treatment were more likely to respond positively to the therapy, while those with primary refractory aggressive B-cell lymphomas showed poor outcomes, indicating that tumor biology plays a significant role in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the input material quality for the production of tisagenlecleucel by multiparameter flow cytometry and its relation to the clinical outcome. Štach, M., Pytlík, R., Šmilauerová, K., et al.[2023]

Tisagenlecleucel is a CAR-T cell therapy effective for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia in pediatric and young adult patients, as well as relapsed/refractory diffuse large B-cell lymphoma in adults.

Nurses play a crucial role in the outpatient administration and post-infusion care of tisagenlecleucel therapy, requiring thorough education on the treatment and adverse event management to ensure effective communication and patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tisagenlecleucel Therapy: Nursing Considerations for the Outpatient Setting. Cunningham, K., DiFilippo, H., Henes, K., et al.[2021]

References

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

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

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

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

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

Evaluating tisagenlecleucel and its potential in the treatment of relapsed or refractory diffuse large B cell lymphoma: evidence to date. [2020]

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

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

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

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. [2019]

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

CAR T Cell Toxicity: Current Management and Future Directions. [2020]

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

Characterization of the input material quality for the production of tisagenlecleucel by multiparameter flow cytometry and its relation to the clinical outcome. [2023]

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

Tisagenlecleucel Therapy: Nursing Considerations for the Outpatient Setting. [2021]