Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Heart and Blood Diseases

Rare Diseases

Leukemia

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Lymphosarcoma

Antipyretics

All Drugs and Chemicals

In the experimental arm, patients will receive a single standard dose of Tocilizumab (Actemra®) 8 mg/kg b.w. intravenously infused over 1 hour in 250 ml NaCl 0.9%, with completion of the infusion 1 hour prior to the infusion of the CAR-T cells. Prior to Tocilizumab administration, no specific premedication is given. The treatment of eventual subsequent CRS will be identical as in patients in the standard arm.

In the standard arm, patients will receive conventional antipyretics and Tocilizumab at first clinical signs (being grade 1 or higher) of emerging CRS. Tocilizumab will be given at the standard-dose of 8 mg/kg b.w. intravenously over one hour in 250 ml NaCl 0.9%, and it will be repeated after 8 hours for a maximum of four administrations in patients with ongoing signs of CRS. Prior to Tocilizumab administration, no specific premedication is given.

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.

Tocilizumab before CAR-T cell infusion

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.

Tocilizumab at emerging CRS

Thomas Pabst, Prof.

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.

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.

Randomized, two arm, open-label, single-center trial.

PRONTO Trial (PRophylactic Versus ON-demand Use of TOcilizumab)

Prospective Comparison Between Prophylactic and On-demand Use of Tocilizumab in CAR-T Recipients - a Randomized, Two Arm, Open-label, Single-center Trial

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

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

Number of days from admission to discharge from hospital

Number of transfusion (erythrocyte) given

Number of admissions to the intensive care unit

Overall survival assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180

Relapse assessment are based on physician's reporting of the assessments of the various disease types involved at day 90 and day 180

daily assessment of IL-6 during the hospitalisation and at day 90 and day 180

Peripheral molecular DNA CAR-T level measurement performed at day 0, day 8 and once a month during months 2 to 6

Insel Gruppe AG, University Hospital Bern

Symptoms and General Pathology

Nervous System Diseases

Substance Related Disorders

Syndrome

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Cytokine Release Syndrome

Neurotoxicity Syndromes

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Antineoplastic Agents

Antirheumatic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10\^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10\^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10\^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.

After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells.

Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.

Three dose levels are being evaluated: dose level -1 (1 x 10\^5), dose level 1 (5 x 10\^5), and dose level 2 ( 1x 10\^6)

iC9-CAR19 cells

Subjects with CRS and ICAN will assign one of two dose levels (DL)s of rimiducid with the standard treatment: 0.05 mg/kg or 0.1 mg/kg for subjects with CRS and 0.01mg/kg or 0.1mg/kg for subjects with ICAN. Subjects will first be enrolled on DL 1 and then enrolled on DL 2, and 0.4mg/kg rimiducid will be given to subjects who did not respond to the initial dose.

Rimiducid

900 mg/m\^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.

25 mg/m\^2/day IV over 30 minutes administered for 3 consecutive days.

Catherine Cheng

Kelly Hoye

Natalie Grover, MD

Natalie S Grover, MD

The body has different ways of fighting infection and disease. No single way is effective at fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to try to create a more effective treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration.

In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying the genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and can find and stick to leukemia cells because these leukemia cells have a substance on their surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood a piece of it is now joined to the surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.

Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging; however, many subjects receiving this treatment have experienced unwanted side effects including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm or an infusion reaction). Cytokines are small proteins that interreact as e signals to other cells and are the way cells talk to one another. During cytokine release syndrome, too many cytokines are released and too many cells in your body react to their release. Symptoms resulting from cytokine release syndrome vary from flu-like symptoms to more severe side effects such as cardiac arrest, multi-system organ failure or death. We predict that about 50% of patients on this study will experience mild to severe cytokine release syndrome.

To help reduce cytokine release syndrome symptoms in future patients, a safety switch has been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells.

The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects). Researchers has previously tested different doses of the iC9-CAR19. An effective dose that had the least number of unwanted side effects in patients was identified. It was planned to test this dose in more patients to learn more about its effect in the body. This type of research study is called a dose expansion study. It will allow the investigators to collect more information about the effect of this dose in treating of certain type of cancer.

LCCC1541-ATL is a Phase I/Phase II dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL).

OUTLINE

Cell Procurement

Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for apheresis will be up to 2 blood volumes.

Lymphodepleting Regimen

Subjects will receive a lymphodepleting regimen of fludarabine 25 mg/m2/day administered IV over 30 min for three consecutive days and a single IV dose of cyclophosphamide 900 mg/m2 administered over 1 hour on the fourth day. If iC9-CAR19 T cell infusion is delayed for \>4 weeks, lymphodepletion may be repeated prior to iC9-CAR19 T cell infusion.

Administration of iC9-CAR19 T Cells

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified. A phase I trial performed by Lee et al established that 1×106 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.

Second Cell Infusion Requirements:

Subjects will be offered a second infusion based on B-cell recovery and MRD status \>4 weeks after the initial infusion if cells are available or if the subject has sufficient stored peripheral blood to manufacture additional iC9-CAR19 T cells.

Duration of Therapy

Therapy in LCCC1541-ATL involves 1 infusion of iC9-CAR19 cells. Treatment with one infusion will be administered unless:

* Subject decides to withdraw from study treatment, or
* General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.

A second infusion with prior lymphodepletion will be given to subjects enrolled in the expansion cohort and to subjects enrolled in the dose escalation cohort once the RP2D is reached if they meet the eligibility requirements for lymphodepletion and infusion. Specifically, only subjects with the following characteristics will be offered a second infusion:

* B-cell recovery (defined as absolute CD19+ cell count \>50/μL in the blood or bone marrow within 6 months of initial infusion AND/OR
* MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with CD19+ expression at any time after the initial infusion.
* \*Note that subjects who receive dose level 1 in the dose escalation will receive the RP2D for their second infusion, if applicable.

Duration of Follow-up

Subjects will be followed for up to 15 years after the final iC9-CAR19 T-cell infusion for RCR evaluation or until death, whichever occurs first. Subjects removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

Subjects who receive new therapy (such as hematopoietic stem cell transplant) after a cell product administration will still be required to complete abbreviated follow up procedures.

Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL

Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).

The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.

Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.

ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm \[defined as minimal residual disease negative complete response\] by either flow cytometry or PCR analysis will be determined)

Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.

Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.

Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.

The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.

Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.

Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.

Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PRONTO Trial (PRophylactic Versus ON-demand Use of TOcilizumab)	NCT06430736	Myeloma Lymphoma Leukemia	Tocilizumab bef... Tocilizumab at ...	18 Years -	Insel Gruppe AG, University Hospital Bern
Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL	NCT03016377	Acute Lymphobla... Immune System D... Immunoprolifera...	iC9-CAR19 cells Rimiducid Cyclophosphamid... Fludarabine	3 Years - 70 Years	UNC Lineberger Comprehensive Cancer Center
PRONTO Trial (PRophylactic Versus ON-demand Use of TOcilizumab)	NCT06430736	Myeloma Lymphoma Leukemia	Tocilizumab bef... Tocilizumab at ...	18 Years -	Insel Gruppe AG, University Hospital Bern

Spots Global Cancer Trial Database for icans

Every month we try and update this database with for icans cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for icans

Every month we try and update this database with for icans cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for icans cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.