Tisagenlecleucel Safety for Cancer
Recruiting in Palo Alto (17 mi)
+54 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Novartis Pharmaceuticals
Disqualifiers: HIV, Hepatitis B, Hepatitis C, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
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?
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.13678
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.13679
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.
See 3 more
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.
See 5 more
Trial 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 (CAR T-cell Therapy)
- Tisagenlecleucel (CAR T-cell Therapy)
Trial OverviewThe 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
3Treatment groups
Experimental Treatment
Group I: Group C: r/r NHLExperimental Treatment1 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 LBCLExperimental Treatment1 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: pALLExperimental Treatment1 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
Find a Clinic Near You
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Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
References
Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia. [2021]The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy.
Express Delivery of Next-Generation CAR T Cells with Preserved Naive and Stemness Phenotypes for the Treatment of Aggressive Lymphomas. [2023]In this issue of Cancer Discovery, Dickinson and colleagues present clinical data from a first-in-human study of YTB323, a novel autologous CD19-directed chimeric antigen receptor T-cell therapy generated on the T-Charge platform with preserved naive state and stemness phenotypes. Treatment with YTB323 achieved high overall response rates, durable complete remissions, and good overall safety. Their cell doses are up to 25-fold lower than with tisagenlecleucel. See related article by Dickinson et al., p. 1982 (10).
Point-of-care CAR T-cell therapy as salvage strategy for out-of-specification tisagenlecleucel. [2023]Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.
Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. [2020]Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).
Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. [2021]Tisagenlecleucel (tisa-cel) is a second-generation autologous CD19-targeted chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa-cel in the standard-of-care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa-cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa-cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non-relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow-up of 14.1 months from CAR T-cell infusion, median progression-free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa-cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.
CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. [2023]Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsed/refractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractory/relapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies.
CD19 CAR T Cells for the Treatment of Pediatric Pre-B Cell Acute Lymphoblastic Leukemia. [2020]The development of cluster of differentiation (CD)-19-targeted chimeric antigen receptor (CAR) T cells for the treatment of pre-B-cell acute lymphoblastic leukemia (B-ALL) is an exciting new advancement in the field of pediatric oncology. Tisagenlecleucel and axicabtagene ciloleucel are the first US FDA-approved CD19-targeted CAR T cells. While various different CD19 CAR T cells are in development, tisagenlecleucel is the only CAR T cell approved for pediatric patients. The multicenter phase II trial that led to the approval of tisagenlecleucel demonstrated excellent responses in individuals with highly refractory disease. Other high-risk groups of patients with B-ALL who experience poor outcomes with standard therapy may also benefit from treatment with tisagenlecleucel. After receiving CAR T cells, patients must be closely monitored for unique toxicities, including cytokine release syndrome, neurotoxicity, and B-cell aplasia. The management of patients with relapsed or refractory disease after administration of CD19 CAR T cells can be challenging, and treatment options vary according to the characteristics of the disease present at relapse. In the many patients who experience a complete response, CAR T cells can lead to a durable remission. This review describes the current design and manufacturing of CAR T cells. Data in the selection and management of pediatric patients are highlighted, as are areas where further studies are needed.
Updated insights on cardiac risks of CD19-directed chimeric antigen receptor T-cell therapy: a pharmacovigilance study. [2023]Aim: Comprehensively characterize the cardiotoxicity of CD19-directed chimeric antigen receptor T-cell (CAR-T) products. Materials & methods: Data between 2017 and 2021 in the US FDA's Adverse Event Reporting System database were utilized. Disproportionality was measured using reporting odds ratio and information component. Hierarchical clustering analysis was performed to explore the relationships among cardiac events. Results: Tisagenlecleucel exhibited the highest percentage of death (53.24%) and life-threatening (13.39%) outcomes. Axicabtagene ciloleucel and tisagenlecleucel were equal in the number of positive signals (n = 15), while the former had excessive reporting of several cardiac events versus the latter, such as atrial fibrillation, cardiomyopathy, cardiorenal syndrome and sinus bradycardia. Conclusion: Several cardiac risks should be considered for CAR-T treatment and these events might vary in frequency and severity following different CAR-T agents.
FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia. [2020]Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD)