Long-Term Follow-Up for CAR-T Therapy Safety (PAVO Trial)
Recruiting in Palo Alto (17 mi)
+79 other locations
Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Novartis Pharmaceuticals
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 3 jurisdictions
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.
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.
78101112How 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.
123414What 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.
568913Will 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.
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.Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Previously treated CAR-T patientsExperimental Treatment1 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
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
University of Michigan Health System SC CTL019Ann Arbor, MI
Stanford University Medical Center SC - CTL019B2205J - B2206Stanford, CA
Childrens Healthcare of Atlanta SC CTL019Atlanta, GA
Beth Israel Deaconess Medical CenteBoston, MA
More Trial Locations
Loading ...
Who is running the clinical trial?
Novartis PharmaceuticalsLead Sponsor
University of PennsylvaniaCollaborator
References
The challenge of follow-up for clinical trials of somatic gene therapy. [2012]Although extensive efforts have been made to optimize the safety of vectors for somatic gene transfer and somatic gene therapy, the safety of these agents must ultimately be assessed in clinical trials. A statistically significant assessment of safety will be complicated by the relatively small number of patients who will be enrolled in initial clinical trials, the need for long-term longitudinal follow-up of patients and perhaps their progeny, and the traditionally poor participation in long-term follow-up by many patients. This article reviews the potential risks of retroviral-mediated gene transfer, the statistical power required to assess the true incidence of potential complications, the number of patients who may participate in clinical trials involving retroviral vectors, and the factors that make thorough follow-up and uniform data ascertainment difficult. The role of the FDA in assessing the safety of retroviral vectors and the potential role of registries for patient tracking and data ascertainment are discussed.
Long-term follow-up of survivors of childhood cancer. [2019]This study was designed to improve the long-term follow-up of childhood cancer survivors by developing standard monitoring for adverse effects; Providing concise treatment summaries for each patient and identifying already existing adverse effects; Determining patient risks for long-term adverse effects; and providing individualized 10-year of plans for follow-up.
Long-term follow-up of people who have survived cancer during childhood. [2016]Substantial improvements in survival after treatment for malignant disease in childhood are leading to a rapidly increasing number of long-term survivors, many of whom are now adults. However, late chronic adverse effects of treatment are common, and have potentially severe effects on survivors' future physical, cognitive, or psychosocial health. The aim of long-term follow-up is to facilitate timely diagnosis and appropriate management of late adverse effects, thereby reducing the frequency of severe complications. Although the delivery of long-term follow-up care varies substantially--particularly in terms of who provides it, where, and how--recognition of the importance of appropriate multidisciplinary care and cross-speciality care is increasing, especially for adolescent and adult survivors of cancer during childhood. Several models of long-term follow-up care have been developed to address this need. This review discusses the present provision of long-term follow-up, and summarises information that might facilitate design and implementation of future models of long-term follow-up care.
Surviving the cure: long term followup of hematopoietic cell transplant recipients. [2022]Advances in hematopoietic cell transplantation (HCT) have led to an increasing number of transplant survivors. However, long-term survival is challenged by late relapse, late complications and late non-relapse mortality, and HCT survivors need continued lifelong surveillance for screening, early detection and timely treatment of late complications such as secondary cancers, late infections and organ toxicity. Guidelines for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT were updated and published in 2012. However, several barriers to the care of HCT survivors and routine utilization of these guidelines in clinical practice exist. Examples include paucity of and challenges to conducting prospective randomized trials for screening and prevention of late complications, lack of resources to manage late effects at the level of transplant centers and community health care providers, and inadequate tools to facilitate care and followup of HCT survivors. We summarize the long-term followup guidelines in this review, discuss ways that providers can integrate and utilize them for the care of their patients, and identify areas for research that can inform and increase the utilization of screening and prevention guidelines in clinical practice.
Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy. [2023]Chimeric antigen receptors (CAR) are engineered fusion proteins constructed from antigen recognition, signaling, and costimulatory domains that can be expressed in cytotoxic T cells with the purpose of reprograming the T cells to specifically target tumor cells. CAR T-cell therapy uses gene transfer technology to reprogram a patient's own T cells to stably express CARs, thereby combining the specificity of an antibody with the potent cytotoxic and memory functions of a T cell. In early-phase clinical trials, CAR T cells targeting CD19 have resulted in sustained complete responses within a population of otherwise refractory patients with B-cell malignancies and, more specifically, have shown complete response rates of approximately 90% in patients with relapsed or refractory acute lymphoblastic leukemia. Given this clinical efficacy, preclinical development of CAR T-cell therapy for a number of cancer indications has been actively investigated, and the future of the CAR T-cell field is extensive and dynamic. Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into the mechanisms regulating the persistence of CAR T cells. In addition, numerous early-phase clinical trials are now investigating CAR T-cell therapy beyond targeting CD19, especially in solid tumors. Trials investigating combinations of CAR T cells with immune checkpoint blockade therapies are now beginning and results are eagerly awaited. This review evaluates several of the ongoing and future directions of CAR T-cell therapy.
Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells. [2021]CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG
Complications after CD19+ CAR T-Cell Therapy. [2020]Clinical trials demonstrated that CD19+ chimeric antigen receptor (CAR) T-cells can be highly effective against a number of malignancies. However, the complete risk profile of CAR T-cells could not be defined in the initial trials. Currently, there is emerging evidence derived from post approval studies in CD19+ CAR T-cells demonstrating both short-term and medium-term effects, which were unknown at the time of regulatory approval. Here, we review the incidence and the current management of CD19+ CAR T-cell complications. We highlight frequently occurring events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cardiotoxicity, pulmonary toxicity, metabolic complications, secondary macrophage-activation syndrome, and prolonged cytopenia. Furthermore, we present evidence supporting the hypothesis that CAR T-cell-mediated toxicities can involve any other organ system and we discuss the potential risk of long-term complications. Finally, we discuss recent pre-clinical and clinical data shedding new light on the pathophysiology of CAR T-cell-related complications.
Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells. [2023]As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.
Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy. [2022]Despite the success of chimeric antigen receptor (CAR) T cells in clinical studies, a significant proportion of responding patients eventually relapsed, with the latter correlating with low CAR T cell expansion and persistence.
Cutaneous manifestations of chimeric antigen receptor T-cell therapy: An introduction for dermatologists. [2022]Chimeric antigen receptor T-cell therapy is an emerging immunotherapy with promising efficacy for the treatment of previously refractory or relapsed malignancies. As a personalized medicine approach, T cells are genetically engineered to express a receptor designed to bind a specific tumor antigen, leading to selective immune-mediated destruction of tumor cells. Due to the novelty of chimeric antigen receptor T-cell therapy, the safety profile continues to evolve with limited information currently available on cutaneous adverse events. Improved understanding of the spectrum of cutaneous adverse events may facilitate earlier recognition and appropriate management of these toxicities. To explore this knowledge gap, we discuss the available case reports and clinical trial results of cutaneous reactions associated with chimeric antigen receptor T-cell therapy.
Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus on Safety. [2022]Serious adverse reactions have been reported with the use of Chimeric Antigen Receptor (CAR) T-cell therapy in a clinical setting despite the success of these products in pre- clinical stages of development.
Toxicities associated with adoptive cellular therapies. [2022]Chimeric antigen receptor (CAR) T cell therapy is an effective strategy for the treatment of relapsed/refractory hematologic malignancies leading to the Food and Drug Administration (FDA) approval of five CAR T cell products. Despite encouraging efficacy, the widespread utilization of CAR T cell therapy is limited by unique immune mediated toxicities, primarily cytokine release syndrome (CRS) and neurologic toxicity. Data regarding late effects and long-term toxicities of CAR T cell therapy is evolving and includes prolonged cytopenias, hypogammaglobulinemia, infections and secondary malignancies. In this review, we will describe the clinical presentation, diagnosis, mechanisms and management of short- and long-term toxicities of CAR T cell therapy.
Supportive care for chimeric antigen receptor T-cell patients. [2023]The purpose of this review is to provide clear guidance to health professionals delivering chimeric antigen receptor T-cell (CAR-T) therapy on the best supportive management throughout the CAR-T pathway, from referral to long-term follow-up, including psychosocial aspects.
Practical and Statistical Considerations for the Long Term Follow-Up of Gene Therapy Trial Participants. [2023]Study sponsors and market authorization holders are required by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to enroll patients administered a gene therapy product, whether in a trial setting or post-licensure, in a long term follow-up safety study to continue the safety assessments of their product. These follow-up studies range between 5 and 15 years after dosing. This unprecedented duration of engagement with patients and caregivers raises logistical challenges that will require innovation and collaboration across sponsors and regulators. In this paper we delineate some of the key considerations for designing long term follow-up protocols in the gene therapy setting, with an eye toward platform and master protocol approaches, and offer guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics.