Leukemia, Lymphoma, Myeloma
Conditions
Keywords
Tocilizumab, Myeloma, Leukemia, Lymphoma, CRS, ICANS
Brief summary
Despite the consequent use of Tocilizumab together with conventional antipyretics at early/first signs of emerging CRS, CRS (and eventually the subsequent development of ICANS) remain a major concern for patients. This study aims to identify safety and efficacy of prophylactic Tocilizumab treatment. In particular, to explore whether prophylactic Tocilizumab treatment can decrease the incidence and severity of CRS (and subsequent eventual neurotoxicity) following CAR-T-treatment.
Detailed description
Adoptive immunotherapy with CD19 (cluster of differentiation antigen 19) targeting chimeric antigen-receptor (CAR-)T cells is an effective therapeutic strategy against relapsed or refractory B-cell malignancies, including B-cell lymphomas, B-ALL (acute lymphoblastic leukemia) and myeloma. Currently, up to 50 commercial CAR-T-cell treatments are performed annually at the Inselspital in Bern, making it by far the largest center for CAR-T cell treatment in Switzerland. CAR-T treatment is associated with well-described acute adverse events, including cytokine release syndrome (CRS) and neurotoxicity, termed immune effector cell associated neurologic syndrome (ICANS). CRS (at all grades) occurs in between 42 to 93% of all patients with variations among available products, and ICANS can occur (at all grades) in 21% up to 64%. Acute complications of CAR-T cell therapy are the result of rapid CAR-T cell expansion and of a hyper-inflammatory state related to cell activation. Interleukin (IL-6) is a central mediator of cytokine-responses in CRS and ICANS together with other cytokines and chemokines involved. IL-6 interacts with its receptor (IL-6R) in either membrane-bound form, leading to classic IL-6 signaling after interacting with GP130, or soluble in plasma, where the IL-6 / IL-6R complex interacts with GP130 expressing cells in trans IL-6 signaling. Tocilizumab is a humanized monoclonal antibody that binds the IL-6R in both its soluble and membrane-bound forms. Tocilizumab treatment has become the standard of care for patients presenting with CRS (at all grades), together with antipyretic treatment (grades 1 or 2 at the regular ward) or with vasoactive and/or ventilation support at the intensive care unit (grades 3 and 4). The study aims to assess the incidence of CRS of all grades, as well as the incidence of ICANS of all grades, the duration of hospitalisation and the need of platelet and erythrocyte transfusion within the first three months after CAR-T treatment in patients receiving prophylactic Tocilizumab compared to patients receiving on-demand Tocilizumab.
Interventions
DRUGTocilizumab before CAR-T cell infusion
Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously, with completion of the infusion 1 hour prior to infusion of CAR-T cells. Treatment of eventual subsequent CRS/ICANS will be identical as in patients in the standard arm.
DRUGTocilizumab at emerging CRS
Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously, and it will be repeated after 8 hours for a maximum of four administrations in patients with ongoing signs of CRS.
Sponsors
Insel Gruppe AG, University Hospital Bern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized, two arm, open-label, single-center trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients planned to receive commercial CAR-T treatment for all registered indications comprising lymphomas, leukemias or myeloma at a single academic center (Bern Inselspital) * With written informed consent * Considered by the investigator to be clinically fit for this treatment * Patients aged ≥18 years
Exclusion criteria
* Previous Tocilizumab treatment within 3 months prior to CAR-T infusion * Patients with treatment with an investigational compound within 8 weeks prior to CAR-T infusion * Women who are pregnant or breast feeding, or women intending to become pregnant during the study period; or participants lacking safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases during study treatment and for a total of 12 months; Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential. * Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant * Previous enrolment into the current study * Enrolment of the investigator, his/her family members, employees and other dependent persons
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of CRS of all grades | 30 days | Number of patients with CRS of any grade according to the ASTCT (American Society for Transplantation and Cellular Therapy ) Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells ; including use of antipyretics |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospitalization duration | 30 days | Number of days from admission to discharge from hospital |
| Erythrocyte transfusion needs | 90 days | Number of transfusion (erythrocyte) given |
| Platelet transfusion needs | 90 days | Number of transfusion (platelet) given |
| Incidence of admissions to the intensive care unit | 30 days | Number of admissions to the intensive care unit |
| Incidence of ICANS of all grades | 30 days | Number of patients with ICANS of any grade according to the ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells ; including use of antipyretics |
| Overall survival rates | 180 days | Overall survival assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180 |
| Progression-free survival rates | 180 days | Relapse assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180 |
| IL-6 to monitor CRS | 180 days | daily assessment of IL-6 during the hospitalisation and at day 90 and day 180 |
| Peripheral molecular CAR-T levels | 180 days | Peripheral molecular DNA CAR-T level measurement performed at day 0, day 8 and once a month during months 2 to 6 |
| Incidence of infections | 90 days | Number of infections per patient |
Countries
Switzerland
Contacts
Primary ContactThomas Pabst, Prof.
Outcome results
None listed