Long-Term Follow-Up for CAR-T Therapy Safety

(PAVO Trial)

Recruiting at 80 trial locations

Overseen By Novartis Pharmaceuticals

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: CAR-T therapy

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Varies per primary protocol

1400 Participants Needed

Trial Summary

What is the purpose of this trial?

Per Health Authorities guidelines for gene therapy medicinal products that utilize integrating vectors (e.g. lentiviral vectors), long term safety and efficacy follow up of treated patients is required. The purpose of this study is to monitor all patients exposed to CAR-T therapied for 15 years following their last CAR-T (e.g. CTL019) infusion to assess the risk of delayed adverse events (AEs), monitor for replication competent lentivirus (RCL) and assess long-term efficacy, including vector persistence.

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 is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the CAR-T treatment?

CAR-T therapy has shown excellent antitumor activity in patients with relapsed or refractory B-cell malignancies, with high response rates and outcomes. In early-phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses in patients with B-cell malignancies, achieving approximately 90% complete response rates in relapsed or refractory acute lymphoblastic leukemia. ^{1 2 3 4 5}

What are the safety concerns associated with CAR-T therapy?

CAR-T therapy can cause side effects like cytokine release syndrome (a severe immune reaction), neurologic toxicity, prolonged low blood cell counts, infections, and possibly secondary cancers. There are also concerns about effects on the heart, lungs, and other organs, and the safety profile is still being studied. ^{2 6 7 8 9}

How is CAR-T therapy different from other treatments?

CAR-T therapy is unique because it involves modifying a patient's own T-cells (a type of immune cell) to better recognize and attack cancer cells, which is different from traditional treatments that use drugs or radiation to target cancer. This personalized approach can lead to long-lasting effects, but it requires careful long-term follow-up to monitor for potential late complications. ^{10 11 12 13 14}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for patients who have previously received CAR-T therapy and consented to long-term follow-up. It includes those who completed or left early from a Novartis-sponsored CAR-T study or a University of Pennsylvania CAR-T trial in collaboration with Novartis.

Inclusion Criteria

You have previously received a type of immunotherapy called CAR-T therapy in a Novartis-sponsored trial or a trial associated with the University of Pennsylvania that uses Novartis' CAR technology.

Patients who have provided informed consent for the long term follow up study prior to their study participation.

Exclusion Criteria

Anyone can participate in this study, there are no specific reasons to exclude someone.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CAR-T cell therapy as part of the primary treatment protocols

Varies per primary protocol

Long-term Follow-up

Participants are monitored for safety and efficacy, including the assessment of delayed adverse events and vector persistence

15 years

Visits at M3, M6, M9, M12, every 6 months up to year 5, then yearly until year 15

Treatment Details

Interventions

• CAR-T

Trial Overview The study monitors the safety and effectiveness of CAR-T therapies over 15 years. It looks for delayed side effects, checks for virus that could replicate (RCL), and evaluates how well the treatment works over time including how long the vector lasts in the body.

Participant Groups

Group I: Previously treated CAR-T patients Experimental Treatment 1 Intervention

Patients who previously were exposed to lentiviral-based CART cell therapy

CAR-T is already approved in United States, European Union, Canada for the following indications:

Approved in United States as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Follicular lymphoma

Approved in European Union as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Follicular lymphoma

Approved in Canada as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal 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

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Findings from Research

Approximately 40% of patients with relapsed/refractory B-cell leukemia or lymphoma achieve durable remission after receiving a single dose of CD19-targeted CAR-T therapy, highlighting its efficacy as a transformative treatment.

CAR-T therapy requires careful management due to potential severe immune side effects and prolonged cytopenias, necessitating comprehensive supportive care and extended hospital stays, especially for older patients with other health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supportive care for chimeric antigen receptor T-cell patients. Springell, D., O'Reilly, M., Roddie, C.[2023]

A multicenter initiative has been established to comprehensively study the extended toxicities and late effects of CAR T cell therapy, focusing on areas such as neurotoxicity, psychosocial impacts, and immune reconstitution.

The initiative aims to create a systematic framework for investigating adverse events related to CAR T cell therapy, which will help optimize treatment strategies and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells. Shalabi, H., Gust, J., Taraseviciute, A., et al.[2023]

In a study of patients who underwent CD19-targeted CAR-T cell therapy for B cell malignancies, 73% were alive and 24% were in complete remission after a median follow-up of 28.1 months, indicating promising long-term efficacy.

The most common late adverse event was hypogammaglobulinemia, affecting 67% of patients, but most late events were not severe, suggesting a generally safe long-term profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. Cordeiro, A., Bezerra, ED., Hirayama, AV., et al.[2021]

CAR T-cell therapy, particularly targeting CD19, has shown remarkable efficacy with approximately 90% complete response rates in patients with relapsed or refractory acute lymphoblastic leukemia, demonstrating its potential as a powerful treatment for B-cell malignancies.

Ongoing research is focused on enhancing the safety and effectiveness of CAR T cells, including exploring their use in solid tumors and in combination with other therapies, indicating a promising future for this innovative cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. Maus, MV., June, CH.[2023]

Priming leukemia-bearing mice with 5-azacytidine (AZA) before CAR T cell therapy significantly enhanced CAR T cell expansion and effectiveness against CD19+ B cell acute lymphoblastic leukemia, as shown in patient-derived xenograft mouse models.

AZA treatment activated immune pathways in leukemia cells, increasing the expression of TNFSF4 (OX40L), which improved CAR T cell targeting and killing of leukemia cells, suggesting that AZA could be a beneficial pre-treatment in clinical CAR T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy. Xu, N., Tse, B., Yang, L., et al.[2022]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

CAR T cell therapy is an effective treatment for relapsed/refractory hematologic cancers, leading to the FDA approval of five products, but it is associated with significant immune-mediated toxicities like cytokine release syndrome (CRS) and neurological issues.

Long-term effects of CAR T cell therapy can include prolonged low blood cell counts, reduced antibody levels, increased risk of infections, and potential development of secondary cancers, highlighting the need for careful monitoring and management of these toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities associated with adoptive cellular therapies. Hansen, DK., Dam, M., Faramand, RG.[2022]

A review of 152 pre-clinical studies on CAR T-cell therapy revealed that only 7.9% were specifically designed to assess or improve safety, indicating a significant gap in safety evaluation prior to clinical use.

Key safety parameters, such as the use of immunocompetent animal models and comprehensive monitoring of physiological responses, were inadequately reported, suggesting that current pre-clinical data may not reliably predict the safety of CAR T-cell therapies in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus on Safety. Maharshi, V., Diksha, D., Gupta, P.[2022]

Chimeric antigen receptor T-cell therapy is a promising immunotherapy that shows effective results in treating cancers that have not responded to other treatments, as it uses genetically engineered T cells to target and destroy tumor cells.

There is a need for more information on the safety profile of this therapy, particularly regarding skin-related side effects, to improve early recognition and management of these adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. Nusbaum, KB., Dulmage, B., Choi, JN., et al.[2022]

The safety of retroviral vectors used in somatic gene therapy must be evaluated through clinical trials, but challenges arise due to the small number of participants and the need for long-term follow-up.

Factors such as low patient participation in follow-up studies and the complexity of assessing potential complications make it difficult to obtain statistically significant safety data, highlighting the importance of regulatory oversight and patient registries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The challenge of follow-up for clinical trials of somatic gene therapy. Ledley, FD., Brody, B., Kozinetz, CA., et al.[2012]

Childhood cancer treatments have led to significant improvements in survival rates, resulting in a growing population of long-term survivors who may face serious late effects from their treatment.

Effective long-term follow-up care is crucial for these survivors to manage potential health issues, and there is an increasing recognition of the need for multidisciplinary and cross-specialty approaches to provide comprehensive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of people who have survived cancer during childhood. Skinner, R., Wallace, WH., Levitt, GA.[2016]

The FDA and EMA require long-term follow-up safety studies for patients receiving gene therapy, lasting between 5 to 15 years, to ensure ongoing safety assessments of these treatments.

Designing these long-term studies presents logistical challenges, necessitating innovative strategies and collaboration between sponsors and regulators to effectively monitor safety and treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical and Statistical Considerations for the Long Term Follow-Up of Gene Therapy Trial Participants. Rohde, M., Huh, S., D'Souza, V., et al.[2023]

Hematopoietic cell transplantation (HCT) survivors require lifelong monitoring for late complications, including secondary cancers and organ toxicity, due to risks associated with long-term survival after transplantation.

Despite updated guidelines for screening and prevention published in 2012, barriers such as lack of resources and challenges in conducting trials hinder the effective implementation of these guidelines in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surviving the cure: long term followup of hematopoietic cell transplant recipients. Majhail, NS., Rizzo, JD.[2022]

A study of 26 long-term childhood cancer survivors revealed that 74% experienced long-term adverse effects from their cancer treatments, highlighting the need for ongoing monitoring.

Common adverse effects included growth hormone deficiency, hypothyroidism, seizures, and hearing loss, emphasizing the importance of individualized 10-year follow-up plans for each patient to manage these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of survivors of childhood cancer. Condren, M., Lubsch, L., Vats, TS.[2019]

References

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

Supportive care for chimeric antigen receptor T-cell patients. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells. [2023]

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

Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. [2021]

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

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. [2023]

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

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Toxicities associated with adoptive cellular therapies. [2022]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus on Safety. [2022]

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

Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. [2022]

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

The challenge of follow-up for clinical trials of somatic gene therapy. [2012]

11. England pubmed.ncbi.nlm.nih.gov

Long-term follow-up of people who have survived cancer during childhood. [2016]

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

Practical and Statistical Considerations for the Long Term Follow-Up of Gene Therapy Trial Participants. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Surviving the cure: long term followup of hematopoietic cell transplant recipients. [2022]

14. India pubmed.ncbi.nlm.nih.gov

Long-term follow-up of survivors of childhood cancer. [2019]